Advertisement

Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease

Open AccessPublished:November 01, 2014DOI:https://doi.org/10.1016/j.jhep.2014.10.039

      Summary

      Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor belonging, together with PPARγ and PPARβ/δ, to the NR1C nuclear receptor subfamily. Many PPARα target genes are involved in fatty acid metabolism in tissues with high oxidative rates such as muscle, heart and liver. PPARα activation, in combination with PPARβ/δ agonism, improves steatosis, inflammation and fibrosis in pre-clinical models of non-alcoholic fatty liver disease, identifying a new potential therapeutic area. In this review, we discuss the transcriptional activation and repression mechanisms by PPARα, the spectrum of target genes and chromatin-binding maps from recent genome-wide studies, paying particular attention to PPARα-regulation of hepatic fatty acid and plasma lipoprotein metabolism during nutritional transition, and of the inflammatory response. The role of PPARα, together with other PPARs, in non-alcoholic steatohepatitis will be discussed in light of available pre-clinical and clinical data.

      Abbreviations:

      PPAR (peroxisome proliferator-activated receptor), FAO (fatty acid oxidation), FA (fatty acid), APR (acute phase response), NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), CVD (cardiovascular disease), LDL (low density lipoprotein), HDL-C (high density lipoprotein cholesterol), SPPARM (selective PPAR modulator), AF-1 (activation function-1), MAPK (mitogen-activated protein kinase), DBD (DNA binding domain), PPRE (PPAR response element), DR-1 (direct repeat-1), RXR (retinoid X receptor), LBD (ligand binding domain), NCoR (nuclear receptor co-repressor), PKC (protein kinase C), SUMO (small ubiquitin-like modifier), AF-2 (activation function-2), LBP (ligand binding pocket), CBP (CREB-binding protein), SRC-1 (steroid receptor coactivator-1), ACOX1 (acyl-CoA oxidase 1), LTB4 (leukotriene B4), 8(S)-HETE (8(S)-hydroxyeicosatetraenoic acid), 8-LOX (8-lipoxygenase), FATP-1 (fatty acid transport protein-1), FAS (fatty acid synthase), 16:0/18:1-GPC (1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine), ATGL (adipose triglyceride lipase), TG (triglyceride), HSL (hormone-sensitive lipase), EC50 (half maximal effective concentration), GAL4 (galactosidase 4), HAT (histone acetyltransferase), PBP (PPARα-binding protein), MED-1 (mediator subunit 1), PPARαDISS (PPARα mutant with selective transrepression activity), LXR (liver X receptor), DR-4 (direct repeat-4), C/EBPα (CCAAT-enhancer-binding protein alpha), TBP (TATA-binding protein), GO (gene ontology), IL-6 (interleukin-6), AP-1 (activator protein 1), NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells), JNK (c-Jun N-terminal protein kinase), GR (glucocorticoid receptor), Fib (fibrinogen), SAA (serum amyloid A), Hg (haptoglobin), CRP (C reactive protein), STAT3 (signal transducer and activator of transcription 3), Fib-β (fibrinogen-beta), GRIP-1/TIF-1 (GR-interactin protein-1/transcription intermediary factor-2), ERR (estrogen-related receptor), SIRT-1 (sirtuin-1), ERRE (ERR response element), LPS (lipopolysaccharide), TNF (tumor necrosis factor), ATP (adenosine triphosphate), LCFA (long-chain fatty acid), VCFA (very long-chain fatty acid), FAT/CD36 (fatty acid translocase), L-FABP (liver fatty acid-binding protein), EHHADH (L-bifunctional enzyme), CPT (carnitine palmitoyltransferase), MCAD (medium-chain acyl-CoA dehydrogenase), LCAD (long-chain acyl-CoA dehydrogenase), VLCAD (very long-chain acyl-CoA dehydrogenase), let-7c (let-7 microRNA precursor), miRNA (microRNA), APO-AI (apolipoprotein-AI), HMGCS (mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase), KD (ketogenic diet), FGF21 (fibroblast growth factor 21), BDH (beta-D-hydroxybutyrate dehydrogenase), LPL (lipoprotein lipase), APO-CIII (apolipoprotein-CIII), ChREBP (carbohydrate-responsive element-binding protein), HNF-4 (hepatocyte nuclear factor 4), FOXO1 (forkhead box O1), APO-AII (apolipoprotein-AII), ChIP-seq (chromatin immunoprecipitation-sequencing), APO-AV (apolipoprotein-AV), SNP (single-nucleotide polymorphism), SREBP-1c (sterol regulatory element binding protein-1c), Acc1 (acetyl-CoA carboxylase 1), Scd-1 (stearoyl-CoA desaturase-1), PKA (protein kinase A), cAMP (cyclic adenosine monophosphate), mTORC1 (mammalian target of rapamycin complex 1), PI3K (phosphoinositide 3-kinase), S6K2 (protein S6 kinase 2), IR (insulin resistance), AMPK (5′-AMP-activated protein kinase), T2DM (type 2 diabetes mellitus), ICAM-1 (intracellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1), IL-1RA (interleukin-1 receptor antagonist), IκB (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor), MetS (metabolic syndrome), MCDD (methionine choline-deficient diet), CYP4A (cytochrome P450 4A), VNN1 (vanin-1), ALMS1 (Alstrom syndrome 1), HFD (high-fat diet), ALT (alanine aminotransferase), APO-E2 (apolipoprotein-E2), ROS (reactive oxygen species), TGFβ (transforming growth factor beta), COX-1 (cyclooxygenase-1), AST (aspartate aminotransferase), γGT (gamma-glutamyl transpeptidase), LDLR (LDL-receptor), ALP (alkaline phosphatase), PUFA (polyunsaturated fatty acid)

      Keywords

      Introduction

      PPARα (NR1C1) is a ligand-activated nuclear receptor highly expressed in the liver, initially identified as the molecular target of xenobiotics inducing peroxisome proliferation in rodents [
      • Issemann I.
      • Green S.
      Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators.
      ]. Beside PPARα, the PPAR subfamily contains two other isotypes encoded by the PPARβ/δ (NR1C2) and PPARγ (NR1C3) genes, each displaying isoform-specific tissue distribution patterns and functions [
      • Kliewer S.A.
      • Forman B.M.
      • Blumberg B.
      • Ong E.S.
      • Borgmeyer U.
      • Mangelsdorf D.J.
      • et al.
      Differential expression and activation of a family of murine peroxisome proliferator-activated receptors.
      ]. PPARα expression is enriched in tissues with high fatty acid oxidation (FAO) rates such as liver, heart, skeletal muscle, brown adipose tissue, and kidney, although it is also expressed in many tissues and cells including the intestine, vascular endothelium, smooth muscle and immune cells such as monocytes, macrophages and lymphocytes [
      • Lefebvre P.
      • Chinetti G.
      • Fruchart J.C.
      • Staels B.
      Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis.
      ]. PPARα is a nutritional sensor, which allows adaptation of the rates of fatty acid (FA) catabolism, lipogenesis and ketone body synthesis, in response to feeding and starvation [
      • Hashimoto T.
      • Cook W.S.
      • Qi C.
      • Yeldandi A.V.
      • Reddy J.K.
      • Rao M.S.
      Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting.
      ]. PPARα is a transcriptional regulator of genes involved in peroxisomal and mitochondrial β-oxidation, FA transport and hepatic glucose production, the latter being rodent-specific [
      • Xu J.
      • Xiao G.
      • Trujillo C.
      • Chang V.
      • Blanco L.
      • Joseph S.B.
      • et al.
      Peroxisome proliferator-activated receptor alpha (PPARalpha) influences substrate utilization for hepatic glucose production.
      ]. PPARα negatively regulates pro-inflammatory and acute phase response (APR) signalling pathways, as seen in rodent models of systemic inflammation, atherosclerosis and non-alcoholic steatohepatitis (NASH) [
      • Gervois P.
      • Kleemann R.
      • Pilon A.
      • Percevault F.
      • Koenig W.
      • Staels B.
      • et al.
      Global suppression of IL-6-induced acute phase response gene expression after chronic in vivo treatment with the peroxisome proliferator-activated receptor-alpha activator fenofibrate.
      ,
      • Ip E.
      • Farrell G.C.
      • Robertson G.
      • Hall P.
      • Kirsch R.
      • Leclercq I.
      Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice.
      ].
      Dyslipidemia and chronic inflammation are frequent features of non-alcoholic fatty liver disease (NAFLD), likely explaining the association between cardiovascular disease (CVD) and NAFLD. However, there is currently no approved NAFLD treatment. In patients with atherogenic dyslipidemia, fibrates acting as synthetic PPARα agonists, lower plasma triglycerides and small dense low density lipoprotein (LDL) particles, and raise high density lipoprotein cholesterol (HDL-C) levels. Fibrates reduce major cardiovascular events, especially in patients with high triglyceride and low HDL-C [
      • Staels B.
      • Maes M.
      • Zambon A.
      Fibrates and future PPARalpha agonists in the treatment of cardiovascular disease.
      ]. Thus PPARα agonists may potentially be useful in the management of NAFLD and co-morbidities such as CVD. PPARα activation, in combination with PPARβ/δ agonism, improves steatosis, inflammation and fibrosis in rodent models of NASH [
      • Staels B.
      • Rubenstrunk A.
      • Noel B.
      • Rigou G.
      • Delataille P.
      • Millatt L.J.
      • et al.
      Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
      ]. Thus, selective and potent PPARα modulators (SPPARMs) and dual PPAR agonists constitute promising strategies for the treatment of NAFLD. In this review, novel mechanistic insights into PPARα action, in hepatic lipid metabolism, under different nutritional states, and its role in liver inflammation and fibrosis are presented. We also summarize the (pre)clinical findings on PPAR agonists under development for NAFLD treatment.

      Functional analysis of PPARα structure

      Canonical structure of PPARα

      The human and mouse PPARα genes, respectively on chromosome 22 and chromosome 15, encode 468 amino acid polypeptides with 91% homology. In both species, the coding DNA sequence spans the 3′ region of exon 3, exons 4–7, and the 5′ extremity of exon 8 [
      • Gearing K.L.
      • Crickmore A.
      • Gustafsson J.A.
      Structure of the mouse peroxisome proliferator activated receptor alpha gene.
      ]. PPARα has a canonical nuclear receptor organization with six domains starting from the N-terminal A/B to the C terminus F domain (Table 1). These domains integrate intracellular signals to control the transcriptional activity of multiple target genes. The A/B domain contains the AF-1 region providing basal, ligand-binding-independent and -dependent activity, which can be potentiated by MAPK phosphorylation of serines 6, 12, and 21 [
      • Barger P.M.
      • Browning A.C.
      • Garner A.N.
      • Kelly D.P.
      P38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: a potential role in the cardiac metabolic stress response.
      ]. Comparative studies of chimeric PPARα/β/γ proteins identified the AF-1 region as a determinant of isotype-specific target gene activation [
      • Hummasti S.
      • Tontonoz P.
      The peroxisome proliferator-activated receptor N-terminal domain controls isotype-selective gene expression and adipogenesis.
      ]. The A/B domain is connected to the DNA binding domain (DBD), harboring two zinc-fingers, which binds PPAR response elements (PPREs), localized in gene regulatory regions and organized as direct repeats of two hexamer core sequences AGG(A/T)CA, separated by one nucleotide (DR-1). PPARα/β/γ bind PPREs uniquely as heterodimers with retinoid X receptor (RXR)α/β/γ [
      • Gearing K.L.
      • Gottlicher M.
      • Teboul M.
      • Widmark E.
      • Gustafsson J.A.
      Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor.
      ]. The A/T rich motif upstream of the DR-1 provides a polarization signal of the PPAR-RXR heterodimer, and may confer isotype-binding specificity. Accordingly, PPARs interact with 5′-extended hexamers, whereas RXR binds to the downstream motif of the response element [
      • Juge-Aubry C.
      • Pernin A.
      • Favez T.
      • Burger A.G.
      • Wahli W.
      • Meier C.A.
      • et al.
      DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance of the 5′-flanking region.
      ]. The hinge region (domain D) is a highly flexible domain linking the DBD (domain C) and the ligand binding domain (LBD). The structural integrity of the hinge region conditions the interaction of PPARα with nuclear receptor corepressors, such as NCoR, in the unliganded conformation [
      • Dowell P.
      • Ishmael J.E.
      • Avram D.
      • Peterson V.J.
      • Nevrivy D.J.
      • Leid M.
      Identification of nuclear receptor corepressor as a peroxisome proliferator-activated receptor alpha interacting protein.
      ]. The hinge region is a target for post-translational modifications, such as phosphorylation catalyzed by PKC on serines 179 and 230. SUMOylation also targets the hinge domain of human PPARα at lysine 185 and potentiates NCoR recruitment [
      • Blanquart C.
      • Mansouri R.
      • Paumelle R.
      • Fruchart J.C.
      • Staels B.
      • Glineur C.
      The protein kinase C signaling pathway regulates a molecular switch between transactivation and transrepression activity of the peroxisome proliferator-activated receptor alpha.
      ,
      • Pourcet B.
      • Pineda-Torra I.
      • Derudas B.
      • Staels B.
      • Glineur C.
      SUMOylation of human peroxisome proliferator-activated receptor alpha inhibits its trans-activity through the recruitment of the nuclear corepressor NCoR.
      ]. The C-terminal LBD is the only domain of PPARα whose structure has been solved by X-ray crystallography [
      • Xu H.E.
      • Lambert M.H.
      • Montana V.G.
      • Plunket K.D.
      • Moore L.B.
      • Collins J.L.
      • et al.
      Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors.
      ]. Similar to PPARγ and PPARβ/δ, the PPARα LBD is composed of a helical sandwich flanking a four-stranded β-sheet and contains the AF-2 helix. The 1400 Å3 volume of the PPARα ligand binding pocket (LBP) is only slightly different than the total volume of the 1600 PPARγ and 1300 Å3 PPARβ/δ LBPs [
      • Gampe Jr., R.T.
      • Montana V.G.
      • Lambert M.H.
      • Miller A.B.
      • Bledsoe R.K.
      • Milburn M.V.
      • et al.
      Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors.
      ,
      • Batista F.A.
      • Trivella D.B.
      • Bernardes A.
      • Gratieri J.
      • Oliveira P.S.
      • Figueira A.C.
      • et al.
      Structural insights into human peroxisome proliferator activated receptor delta (PPAR-delta) selective ligand binding.
      ]. Nevertheless, the PPARα LBP is more lipophilic and less solvent-exposed than the LBPs of the other PPARs, hence allowing the binding of more saturated FA. In contrast to PPARγ, the PPARα AF-2 helix is more tightly packed against the LBD core when complexed with an agonist [
      • Cronet P.
      • Petersen J.F.
      • Folmer R.
      • Blomberg N.
      • Sjoblom K.
      • Karlsson U.
      • et al.
      Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family.
      ]. Crystallography identified tyrosine 314 as the main determinant of isotype ligand-specificity [
      • Xu H.E.
      • Lambert M.H.
      • Montana V.G.
      • Plunket K.D.
      • Moore L.B.
      • Collins J.L.
      • et al.
      Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors.
      ]. The AF-2 domain undergoes ligand-dependent conformational changes, thereby directing various co-activators such as CBP/p300 and SRC-1, carrying LXXLL motifs (L–leucine, X–any amino acid), to a hydrophobic cleft on the PPARα LBD surface, thus promoting the formation of an active transcriptional complex. The AF-2 domain may also play a role in ligand-dependent gene repression. Agonist binding unmasks lysine 358 in the LBD for SUMOylation, hence conferring repressive activity to PPARα [
      • Leuenberger N.
      • Pradervand S.
      • Wahli W.
      Sumoylated PPARalpha mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice.
      ].
      Table 1Functional analysis of PPARα structural domains.
      PPARα displays a classical NR canonical architecture. PPARα domains (from A to F) fulfil distinct functions by providing interaction surfaces with other TFs, co-regulators and ligands, thus contributing to specific PPARα transcriptional regulation. PPARα undergoes several post-translational modifications (PTM) that markedly impact receptor function (details in the text).

      Endogenous and synthetic PPARα agonists

      PPARα ligands are FA derivatives formed during lipolysis, lipogenesis or FA catabolism. Substrates of the first rate-limiting peroxisomal β-oxidation enzyme, acyl-CoA oxidase 1 (ACOX1), likely are PPARα agonists. Consistently, disruption of ACOX1 in mice results in increased peroxisome proliferation, hepatocarcinoma and elevated PPARα target gene expression [
      • Fan C.Y.
      • Pan J.
      • Chu R.
      • Lee D.
      • Kluckman K.D.
      • Usuda N.
      • et al.
      Hepatocellular and hepatic peroxisomal alterations in mice with a disrupted peroxisomal fatty acyl-coenzyme A oxidase gene.
      ,
      • Fan C.Y.
      • Pan J.
      • Usuda N.
      • Yeldandi A.V.
      • Rao M.S.
      • Reddy J.K.
      Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase. Implications for peroxisome proliferator-activated receptor alpha natural ligand metabolism.
      ]. Eicosanoid derivatives, including the chemoattractant LTB4 and 8(S)-HETE, the murine 8-LOX product from arachidonic acid, are thought to be endogenous PPARα agonists [
      • Yu K.
      • Bayona W.
      • Kallen C.B.
      • Harding H.P.
      • Ravera C.P.
      • McMahon G.
      • et al.
      Differential activation of peroxisome proliferator-activated receptors by eicosanoids.
      ]. The oxidized phospholipid fraction of oxidized LDL enhances PPARα transcriptional activity and induces its target gene, FATP-1, in human primary endothelial cells [
      • Delerive P.
      • Furman C.
      • Teissier E.
      • Fruchart J.
      • Duriez P.
      • Staels B.
      Oxidized phospholipids activate PPARalpha in a phospholipase A2-dependent manner.
      ]. Liver-specific knockout of fatty acid synthase (FAS), an enzyme catalysing the synthesis of FA, resulted in hypoglycemia and liver steatosis when mice were fed a fatdepleted diet, which was reversed by dietary fat or a synthetic PPARα agonist, identifying products of FAS-dependent de novo lipogenesis as PPARα activators [
      • Chakravarthy M.V.
      • Pan Z.
      • Zhu Y.
      • Tordjman K.
      • Schneider J.G.
      • Coleman T.
      • et al.
      “New” hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis.
      ]. Mass spectrometry analysis on purified hepatic PPARα revealed the presence of 16:0/18:1-GPC bound to its LBD in mice expressing hepatic FAS, but not in liver-specific FAS knockout mice, identifying this phospholipid as a FAS-dependent lipid intermediate and endogenous PPARα ligand [
      • Chakravarthy M.V.
      • Lodhi I.J.
      • Yin L.
      • Malapaka R.R.
      • Xu H.E.
      • Turk J.
      • et al.
      Identification of a physiologically relevant endogenous ligand for PPARalpha in liver.
      ]. Adipose triglyceride lipase (ATGL)-dependent hydrolysis of hepatic intracellular TG also yields lipid PPARα ligands [
      • Sapiro J.M.
      • Mashek M.T.
      • Greenberg A.S.
      • Mashek D.G.
      Hepatic triacylglycerol hydrolysis regulates peroxisome proliferator-activated receptor alpha activity.
      ]. In line, overexpression of hepatic hormone-sensitive lipase (HSL) and ATGL triggers PPARα-dependent FAO gene expression and ameliorates hepatic steatosis [
      • Reid B.N.
      • Ables G.P.
      • Otlivanchik O.A.
      • Schoiswohl G.
      • Zechner R.
      • Blaner W.S.
      • et al.
      Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis.
      ].
      A range of synthetic PPARα agonists, differing in species-specific potencies and efficacies, have been identified. Fibrates such as gemfibrozil, fenofibrate and ciprofibrate, are clinically used in the treatment of primary hypertriglyceridemia or mixed dyslipidemia [
      • Staels B.
      • Maes M.
      • Zambon A.
      Fibrates and future PPARalpha agonists in the treatment of cardiovascular disease.
      ]. However, fibrates are weak PPARα agonists with limited clinical efficacy [
      • Fruchart J.C.
      Selective peroxisome proliferator-activated receptor alpha modulators (SPPARMalpha): the next generation of peroxisome proliferator-activated receptor alpha-agonists.
      ]. Moreover, the potency of synthetic PPARα agonists may differ between the human and mouse receptor, as measured by using the PPARα-GAL4 transactivation system, i.e., fenofibrate (mouse receptor, EC50 = 18,000 nM vs. human receptor, EC50 = 30,000 nM), bezafibrate (EC50 = 90,000 nM vs. 50,000 nM, respectively) and Wy14,643 (EC50 = 630 nM vs. 5000 nM, respectively) [
      • Willson T.M.
      • Brown P.J.
      • Sternbach D.D.
      • Henke B.R.
      The PPARs: from orphan receptors to drug discovery.
      ]. This may contribute to interspecies differences in response to PPARα agonists that are detailed in the following sections of this review. Potent and selective PPARα modulators (SPPARMs), such as K-877 (EC50 = 1 nM) and GFT505 (EC50 = 6 nM for PPARα), a dual PPARα/δ agonist, are currently under development for the treatment of atherogenic dyslipidemia and NAFLD, respectively [
      • Fruchart J.C.
      Selective peroxisome proliferator-activated receptor alpha modulators (SPPARMalpha): the next generation of peroxisome proliferator-activated receptor alpha-agonists.
      ,
      • Willson T.M.
      • Brown P.J.
      • Sternbach D.D.
      • Henke B.R.
      The PPARs: from orphan receptors to drug discovery.
      ,
      • Cariou B.
      • Staels B.
      GFT505 for the treatment of nonalcoholic steatohepatitis and type 2 diabetes.
      ]. The therapeutic potential of novel PPAR agonists on NAFLD is further discussed in this review.

      Mechanism of PPARα-dependent transactivation

      Formation of transcriptionally active multiprotein PPARα complexes

      Ligand-activated PPARα recruits numerous co-activator proteins, including members of the CBP/p300 and SRC/p160 family, which exhibit HAT activity, and other co-activators forming the transcriptionally active PPARα-interacting cofactor complex [
      • Surapureddi S.
      • Yu S.
      • Bu H.
      • Hashimoto T.
      • Yeldandi A.V.
      • Kashireddy P.
      • et al.
      Identification of a transcriptionally active peroxisome proliferator-activated receptor alpha -interacting cofactor complex in rat liver and characterization of PRIC285 as a coactivator.
      ]. Such interactions are not seen with a PPARα AF-2 domain deleted mutant [
      • Pawlak M.
      • Bauge E.
      • Bourguet W.
      • De Bosscher K.
      • Lalloyer F.
      • Tailleux A.
      • et al.
      The transrepressive activity of Pparalpha is necessary and sufficient to prevent liver fibrosis.
      ]. Disruption of the Pbp/Med1 gene showed its essential role in PPARα-dependent gene regulation. PBP/MED1 stabilizes and directs a large transcription initiation complex containing numerous co-activators and RNA polymerase II to the DNA-bound PPAR-RXR heterodimer [
      • Jia Y.
      • Qi C.
      • Kashireddi P.
      • Surapureddi S.
      • Zhu Y.J.
      • Rao M.S.
      • et al.
      Transcription coactivator PBP, the peroxisome proliferator-activated receptor (PPAR)-binding protein, is required for PPARalpha-regulated gene expression in liver.
      ] (Fig. 1A). However, RXR homodimers may bind DR-1 PPREs independent of PPARα and induce PPARα target gene transcription through a co-activator-dependent mechanism [
      • IJpenberg A.
      • Tan N.S.
      • Gelman L.
      • Kersten S.
      • Seydoux J.
      • Xu J.
      • et al.
      In vivo activation of PPAR target genes by RXR homodimers.
      ]. Recently, using a PPARα mutant (PPARαDISS), which lacks PPRE-binding activity but maintains interactions with RXR and transcriptional co-regulators, we showed that PPARα-driven transactivation depends on PPRE binding in vitro, in human hepatoma HepG2 cells and in vivo in Pparα-deficient mice with liver-specific PPARαDISS expression [
      • Pawlak M.
      • Bauge E.
      • Bourguet W.
      • De Bosscher K.
      • Lalloyer F.
      • Tailleux A.
      • et al.
      The transrepressive activity of Pparalpha is necessary and sufficient to prevent liver fibrosis.
      ].
      Figure thumbnail gr1
      Fig. 1Models of PPARα transcriptional regulation. Several models of PPARα transcriptional regulation have been proposed, via which PPARα modulates expression of its target genes as well as pro-inflammatory transcription factors and acute phase response genes. (A) Formation of the PPRE-dependent ligand-activated transcriptional complex containing PPARα-RXR heterodimer, co-activators, HAT, PBP/MED1 and the transcriptional preinitiation complex (PIC). (B) PPRE-dependent inhibition of NFκB transcriptional activity. Upon ligand activation, DNA-bound PPARα directly interacts with p65 to abolish its binding to an NFκB response element (NRE) in the complement C3 promoter. (C) PPARα directly interacts with pro-inflammatory transcription factors cJun and p65 to negatively regulate their target genes by a mechanism that is thought to be PPRE-independent. (D) Simultaneous ligand-activation of GR and PPARα leads to the enhanced repression of TNF-induced IL-6 transcriptional activity, by the mechanism that stems from a direct GR-PPARα physical interaction. (E) PPARα downregulates fibrinogen β transcriptional activity via ligand-dependent mechanisms, engaging physical interaction between PPARα and GRIP-1/TIF-2.

      Genome-wide transcriptomic and PPARα chromatin binding maps

      Genome-wide localization and activity-occupancy studies revealed that induction of PPARα target gene expression by PPARα agonists is associated with increased binding of PPARα to chromatin, rather by strengthening affinity and stability of existing interactions, than creating de novo ligand-inducible binding regions [
      • Boergesen M.
      • Pedersen T.A.
      • Gross B.
      • van Heeringen S.J.
      • Hagenbeek D.
      • Bindesboll C.
      • et al.
      Genome-wide profiling of liver X receptor, retinoid X receptor, and peroxisome proliferator-activated receptor alpha in mouse liver reveals extensive sharing of binding sites.
      ]. Interestingly, almost half of the PPARα-binding regions in human hepatoma cells are located within introns, whereas only 26% of them are localized in close vicinity (<2.5 kb) of the transcription start site [
      • van der Meer D.L.
      • Degenhardt T.
      • Vaisanen S.
      • de Groot P.J.
      • Heinaniemi M.
      • de Vries S.C.
      • et al.
      Profiling of promoter occupancy by PPARalpha in human hepatoma cells via ChIP-chip analysis.
      ]. In addition, genome-wide profiling of liver X receptor (LXR), RXR, and PPARα in the mouse liver showed overlapping chromatin binding regions of LXR-RXR and PPARα-RXR heterodimers. Nevertheless, only a few percent of LXR and PPARα binding sites contain consensus DR-4 and DR-1 elements, respectively [
      • Boergesen M.
      • Pedersen T.A.
      • Gross B.
      • van Heeringen S.J.
      • Hagenbeek D.
      • Bindesboll C.
      • et al.
      Genome-wide profiling of liver X receptor, retinoid X receptor, and peroxisome proliferator-activated receptor alpha in mouse liver reveals extensive sharing of binding sites.
      ]. De novo motif analysis showed co-enrichment of PPARα-binding regions in C/EBPα and TBP motifs, suggesting that PPARα may influence gene expression through the formation of complexes with other transcription factors [
      • van der Meer D.L.
      • Degenhardt T.
      • Vaisanen S.
      • de Groot P.J.
      • Heinaniemi M.
      • de Vries S.C.
      • et al.
      Profiling of promoter occupancy by PPARalpha in human hepatoma cells via ChIP-chip analysis.
      ]. Interestingly, PPARα chromatin binding mapping, combined with transcriptomics in primary human hepatocytes treated with the synthetic PPARα agonist Wy14,643, showed that genes whose promoter regulatory regions are directly bound by PPARα via PPREs, are on average more strongly upregulated than genes in which PPARα binds to the DNA indirectly [
      • McMullen P.D.
      • Bhattacharya S.
      • Woods C.G.
      • Sun B.
      • Yarborough K.
      • Ross S.M.
      • et al.
      A map of the PPARalpha transcription regulatory network for primary human hepatocytes.
      ]. Comparative transcriptomic studies in primary hepatocytes treated with Wy14,643 revealed only partial overlap of up- (∼20%) or downregulated (∼12%) genes upon PPARα activation, between humans and mice [
      • Rakhshandehroo M.
      • Hooiveld G.
      • Muller M.
      • Kersten S.
      Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human.
      ]. Nevertheless, searching for enriched biological themes, in human and mouse sets of regulated genes by gene ontology (GO) classification, showed a 50% conservation in over-represented GO categories, mostly corresponding to lipid metabolic pathways [
      • Rakhshandehroo M.
      • Hooiveld G.
      • Muller M.
      • Kersten S.
      Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human.
      ]. Importantly, the glycolytic and gluconeogenic pathways were specifically upregulated in mice, whereas xenobiotic metabolism and apolipoprotein synthesis pathways rather in human hepatocytes [
      • Rakhshandehroo M.
      • Hooiveld G.
      • Muller M.
      • Kersten S.
      Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human.
      ,
      • Rakhshandehroo M.
      • Sanderson L.M.
      • Matilainen M.
      • Stienstra R.
      • Carlberg C.
      • de Groot P.J.
      • et al.
      Comprehensive analysis of PPARalpha-dependent regulation of hepatic lipid metabolism by expression profiling.
      ].

      Models of PPARα transcriptional repression

      PPRE-independent transcriptional repression

      PPARα negatively regulates pro-inflammatory signalling pathways via protein-protein interactions, a tethering mechanism extensively studied in vitro and in mouse models of acute inflammation. Ligand-activated PPARα represses cytokine-induced IL-6 gene expression via interference with AP-1 and NFκB signalling pathways. PPARα-driven transrepression involves direct physical interactions between PPARα, the p65 Rel homology domain, and the N-terminus JNK-responsive part of cJun (Fig. 1C) [
      • Delerive P.
      • De Bosscher K.
      • Besnard S.
      • Vanden Berghe W.
      • Peters J.M.
      • Gonzalez F.J.
      • et al.
      Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1.
      ]. Moreover, synergistic transrepression of NFκB-driven gene expression occurs upon simultaneous activation of PPARα and glucocorticoid receptor (GR), a well-characterized NFκB repressor (Fig. 1D) [
      • Bougarne N.
      • Paumelle R.
      • Caron S.
      • Hennuyer N.
      • Mansouri R.
      • Gervois P.
      • et al.
      PPARalpha blocks glucocorticoid receptor alpha-mediated transactivation but cooperates with the activated glucocorticoid receptor alpha for transrepression on NF-kappaB.
      ]. However, PPARα and GR transrepress distinct but overlapping sets of genes in vascular endothelial cells [
      • Xu X.
      • Otsuki M.
      • Saito H.
      • Sumitani S.
      • Yamamoto H.
      • Asanuma N.
      • et al.
      PPARalpha and GR differentially down-regulate the expression of nuclear factor-kappaB-responsive genes in vascular endothelial cells.
      ]. PPARα activation downregulates hepatic APR genes, such as Fib, Saa, and Hg in rodents, and CRP in human hepatocytes. Mechanistically, PPARα downregulates mRNA and protein levels of GP80 and GP130, components of the IL6-receptor, thus disrupting the STAT3 and cJun signalling pathways involved in the APR [
      • Gervois P.
      • Kleemann R.
      • Pilon A.
      • Percevault F.
      • Koenig W.
      • Staels B.
      • et al.
      Global suppression of IL-6-induced acute phase response gene expression after chronic in vivo treatment with the peroxisome proliferator-activated receptor-alpha activator fenofibrate.
      ]. Similarly, in the liver, fibrates downregulate IL-6-stimulated Fib-β expression via PPARα-dependent titration of GRIP-1/TIF-2, thus interfering with C/EBPβ activity (Fig. 1E) [
      • Gervois P.
      • Vu-Dac N.
      • Kleemann R.
      • Kockx M.
      • Dubois G.
      • Laine B.
      • et al.
      Negative regulation of human fibrinogen gene expression by peroxisome proliferator-activated receptor alpha agonists via inhibition of CCAAT box/enhancer-binding protein beta.
      ]. Another mechanism of PPARα-dependent transcriptional repression occurs in the control of ERR-driven mitochondrial respiration and cardiac contraction, where a PPARα-SIRT1 complex binds directly to a single hexameric ERRE motif, thus competitively downregulating ERR target genes [
      • Oka S.
      • Alcendor R.
      • Zhai P.
      • Park J.Y.
      • Shao D.
      • Cho J.
      • et al.
      PPARalpha-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway.
      ,
      • Oka S.
      • Zhai P.
      • Alcendor R.
      • Park J.Y.
      • Tian B.
      • Sadoshima J.
      Suppression of ERR targets by a PPARalpha/Sirt1 complex in the failing heart.
      ]. Recently, we showed that hepatic PPARα represses cytokine- and LPS-induced inflammatory responses in vitro and in vivo, independently of direct DNA binding [
      • Pawlak M.
      • Bauge E.
      • Bourguet W.
      • De Bosscher K.
      • Lalloyer F.
      • Tailleux A.
      • et al.
      The transrepressive activity of Pparalpha is necessary and sufficient to prevent liver fibrosis.
      ].

      Regulation of fatty acid metabolism by PPARα

      PPARα-regulated FA transport and oxidation

      FA are transported in cells by membrane-associated FATPs [
      • Schaffer J.E.
      • Lodish H.F.
      Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein.
      ]. FATP1, which catalyses ATP-dependent esterification of LCFA and VCFA into acyl-CoA derivatives, is a direct PPARα target gene [
      • Martin G.
      • Schoonjans K.
      • Lefebvre A.M.
      • Staels B.
      • Auwerx J.
      Coordinate regulation of the expression of the fatty acid transport protein and acyl-CoA synthetase genes by PPARalpha and PPARgamma activators.
      ,
      • Frohnert B.I.
      • Hui T.Y.
      • Bernlohr D.A.
      Identification of a functional peroxisome proliferator-responsive element in the murine fatty acid transport protein gene.
      ]. Another plasma membrane FA transporter, FAT/CD36, is positively regulated by PPARα ligands [
      • Motojima K.
      • Passilly P.
      • Peters J.M.
      • Gonzalez F.J.
      • Latruffe N.
      Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner.
      ]. Functional PPREs were identified within the promoter of the intracellular lipid trafficking L-Fabp [
      • Helledie T.
      • Grontved L.
      • Jensen S.S.
      • Kiilerich P.
      • Rietveld L.
      • Albrektsen T.
      • et al.
      The gene encoding the Acyl-CoA-binding protein is activated by peroxisome proliferator-activated receptor gamma through an intronic response element functionally conserved between humans and rodents.
      ]. Direct protein-protein interaction were reported between PPARα and L-FABP, suggesting that L-FABP may channel PPARα ligands to the receptor [
      • Hostetler H.A.
      • McIntosh A.L.
      • Atshaves B.P.
      • Storey S.M.
      • Payne H.R.
      • Kier A.B.
      • et al.
      L-FABP directly interacts with PPARalpha in cultured primary hepatocytes.
      ,
      • Velkov T.
      Interactions between human liver fatty acid binding protein and peroxisome proliferator activated receptor selective drugs.
      ]. Consistently, a positive correlation between L-FABP protein and PPRE-driven gene transcription was observed in human hepatoma HepG2 cells, treated with PPARα agonists [
      • Wolfrum C.
      • Borrmann C.M.
      • Borchers T.
      • Spener F.
      Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha – and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus.
      ].
      PPARα controls gene expression levels of the rate-limiting enzymes of peroxisomal β-oxidation, including ACOX1 and EHHADH, most pronouncedly in rodents [
      • Rakhshandehroo M.
      • Hooiveld G.
      • Muller M.
      • Kersten S.
      Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human.
      ]. In rodents and primates, FA transport across the mitochondrial membrane is triggered by PPRE-dependent regulation of CPT-I and CPT-II, which proteins are localized in the outer and inner mitochondrial membrane respectively [
      • Louet J.F.
      • Chatelain F.
      • Decaux J.F.
      • Park E.A.
      • Kohl C.
      • Pineau T.
      • et al.
      Long-chain fatty acids regulate liver carnitine palmitoyltransferase I gene (L-CPT I) expression through a peroxisome-proliferator-activated receptor alpha (PPARalpha)-independent pathway.
      ,
      • Mascaro C.
      • Acosta E.
      • Ortiz J.A.
      • Marrero P.F.
      • Hegardt F.G.
      • Haro D.
      Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor.
      ,
      • Barrero M.J.
      • Camarero N.
      • Marrero P.F.
      • Haro D.
      Control of human carnitine palmitoyltransferase II gene transcription by peroxisome proliferator-activated receptor through a partially conserved peroxisome proliferator-responsive element.
      ]. Moreover, PPARα regulates the critical reaction of mitochondrial β-oxidation by directly controlling MCAD, LCAD, and VLCAD expression levels [
      • Gulick T.
      • Cresci S.
      • Caira T.
      • Moore D.D.
      • Kelly D.P.
      The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression.
      ,
      • Aoyama T.
      • Peters J.M.
      • Iritani N.
      • Nakajima T.
      • Furihata K.
      • Hashimoto T.
      • et al.
      Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha).
      ].
      Enhanced expression of peroxisomal genes involved in lipid metabolism is related to the induction of peroxisome proliferation by PPARα agonists, which may contribute to tumorigenesis in rodents [
      • Reddy J.K.
      • Azarnoff D.L.
      • Hignite C.E.
      Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens.
      ]. A comparative study between mouse and human PPARα expressed in Pparα-deficient mice revealed that Wy14,643 induces mouse liver peroxisomal proliferation in a receptor species-independent manner [
      • Yu S.
      • Cao W.Q.
      • Kashireddy P.
      • Meyer K.
      • Jia Y.
      • Hughes D.E.
      • et al.
      Human peroxisome proliferator-activated receptor alpha (PPARalpha) supports the induction of peroxisome proliferation in PPARalpha-deficient mouse liver.
      ]. However, long-term Wy14,643 treatment induced liver tumors only in 5% of PPARα humanized mice, whereas the incidence of hepatocellular carcinoma was 71% in wild-type mice [
      • Morimura K.
      • Cheung C.
      • Ward J.M.
      • Reddy J.K.
      • Gonzalez F.J.
      Differential susceptibility of mice humanized for peroxisome proliferator-activated receptor alpha to Wy-14,643-induced liver tumorigenesis.
      ]. Mechanistically, murine but not human PPARα downregulated the expression of let-7C, an miRNA targeting the c-myc oncogen [
      • Shah Y.M.
      • Morimura K.
      • Yang Q.
      • Tanabe T.
      • Takagi M.
      • Gonzalez F.J.
      Peroxisome proliferator-activated receptor alpha regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation.
      ]. Moreover, long-term treatment of hyperlipidemic patients with either gemfibrozil or fenofibrate showed no effect on peroxisomal proliferation and hepatocyte hyperplasia, as assessed by light and electron microscopy of liver biopsies [
      • De La Iglesia F.A.
      • Lewis J.E.
      • Buchanan R.A.
      • Marcus E.L.
      • McMahon G.
      Light and electron microscopy of liver in hyperlipoproteinemic patients under long-term gemfibrozil treatment.
      ,
      • Blumcke S.
      • Schwartzkopff W.
      • Lobeck H.
      • Edmondson N.A.
      • Prentice D.E.
      • Blane G.F.
      Influence of fenofibrate on cellular and subcellular liver structure in hyperlipidemic patients.
      ]. Importantly, a meta-analysis of long-term randomized controlled trials demonstrated neutral effects of fibrate treatment on cancer [
      • Bonovas S.
      • Nikolopoulos G.K.
      • Bagos P.G.
      Use of fibrates and cancer risk: a systematic review and meta-analysis of 17 long-term randomized placebo-controlled trials.
      ].

      PPARα and ketogenesis

      During fasting, hepatic FAO increases, yielding acetyl-CoA which is further converted into ketone bodies. Ligand-activated PPARα upregulates mitochondrial HMGCS, a rate-limiting enzyme of ketogenesis, which catalyses condensation of acetyl-CoA and acetoacetyl-CoA to generate HMG-CoA and CoA [
      • Rodriguez J.C.
      • Gil-Gomez G.
      • Hegardt F.G.
      • Haro D.
      Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids.
      ]. The mild phenotype of Pparα-deficient mice fed ad libitum became more pronounced during fasting, being characterized by impaired FAO, lipid accumulation in liver and heart as well as hypoglycemia and an inability to augment ketone body synthesis [
      • Kersten S.
      • Seydoux J.
      • Peters J.M.
      • Gonzalez F.J.
      • Desvergne B.
      • Wahli W.
      Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting.
      ,
      • Djouadi F.
      • Weinheimer C.J.
      • Saffitz J.E.
      • Pitchford C.
      • Bastin J.
      • Gonzalez F.J.
      • et al.
      A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor alpha-deficient mice.
      ]. Moreover, high-fat, low-carbohydrate ketogenic diet (KD)-feeding increased hepatic mRNA expression and plasma levels of FGF21, in parallel with PPARα induction [
      • Badman M.K.
      • Pissios P.
      • Kennedy A.R.
      • Koukos G.
      • Flier J.S.
      • Maratos-Flier E.
      Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states.
      ]. Fgf21 knock-down in KD-fed mice impaired hepatic expression of FAO genes (Acox1, Cpt-I) and ketogenesis (Hmgcs, Bdh), indicating that FGF21 is required for the activation of these metabolic pathways [
      • Badman M.K.
      • Pissios P.
      • Kennedy A.R.
      • Koukos G.
      • Flier J.S.
      • Maratos-Flier E.
      Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states.
      ]. Further studies identified FGF21 as a direct PPARα target gene, induced, in mice and humans, in response to fasting and upon PPARα ligand administration [
      • Badman M.K.
      • Pissios P.
      • Kennedy A.R.
      • Koukos G.
      • Flier J.S.
      • Maratos-Flier E.
      Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states.
      ,
      • Galman C.
      • Lundasen T.
      • Kharitonenkov A.
      • Bina H.A.
      • Eriksson M.
      • Hafstrom I.
      • et al.
      The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man.
      ].

      PPARα in the regulation of hepatic lipid and plasma lipoprotein metabolism

      Molecular insights into the lipid normalizing effects of PPARα

      In rodent models, the reduction of plasma TG-rich lipoprotein upon PPARα activation is related to enhanced FA uptake, conversion into acyl-CoA derivatives, and further catabolism via the β-oxidation pathways. Moreover, the TG-lowering action of PPARα is also due to increased lipolysis via induction of lipoprotein lipase (LPL), which catalyses the hydrolysis of lipoprotein TG into free FA and monoacylglycerol. PPARα controlled LPL mRNA through binding to a PPRE in the human and mouse LPL gene promoters [
      • Schoonjans K.
      • Peinado-Onsurbe J.
      • Lefebvre A.M.
      • Heyman R.A.
      • Briggs M.
      • Deeb S.
      • et al.
      PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene.
      ]. Furthermore, PPARα enhanced LPL activity indirectly by decreasing mRNA levels and secretion of hepatic APO-CIII, an LPL inhibitor [
      • Hertz R.
      • Bishara-Shieban J.
      • Bar-Tana J.
      Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III.
      ]. Interestingly, glucose induced APO-CIII transcription in hepatocytes through a mechanism involving the transcription factors ChREBP and HNF-4 [
      • Caron S.
      • Verrijken A.
      • Mertens I.
      • Samanez C.H.
      • Mautino G.
      • Haas J.T.
      • et al.
      Transcriptional activation of apolipoprotein CIII expression by glucose may contribute to diabetic dyslipidemia.
      ]. Conversely, hepatic expression of APO-CIII was inhibited by insulin through insulin-dependent phosphorylation of FOXO1, resulting in its displacement from the nucleus and inability to drive APO-CIII transcriptional activity [
      • Altomonte J.
      • Cong L.
      • Harbaran S.
      • Richter A.
      • Xu J.
      • Meseck M.
      • et al.
      Foxo1 mediates insulin action on apoC-III and triglyceride metabolism.
      ]. In hepatocytes, inhibition of APO-CIII transcription by fibrates was the consequence of multiple cooperative mechanisms including PPARα-driven displacement of HNF-4 from the APO-CIII promoter, inhibition of FOXO1 activation of APO-CIII transcription via the insulin-responsive element, and inhibition of glucose-stimulated APO-CIII expression [
      • Hertz R.
      • Bishara-Shieban J.
      • Bar-Tana J.
      Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III.
      ,
      • Qu S.
      • Su D.
      • Altomonte J.
      • Kamagate A.
      • He J.
      • Perdomo G.
      • et al.
      PPAR{alpha} mediates the hypolipidemic action of fibrates by antagonizing FoxO1.
      ].
      In humans, fibrates increase plasma HDL-C by stimulating the synthesis of its major apolipoproteins, APO-AI and APO-AII. However, species-differences exist between humans and rodents with respect to apolipoprotein regulation by PPARα. A functional PPRE is present in the human, but not rodent APO-AI promoter, as illustrated by increased human APO-AI production in humanized Apo-AI transgenic mice upon treatment with fibrates [
      • Berthou L.
      • Duverger N.
      • Emmanuel F.
      • Langouet S.
      • Auwerx J.
      • Guillouzo A.
      • et al.
      Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice.
      ]. In contrast, APO-AI and HDL-C levels are elevated in Pparα-deficient mice and fibrate treatment decreases Apo-AI mRNA in wild-type animals [
      • Staels B.
      • van Tol A.
      • Andreu T.
      • Auwerx J.
      Fibrates influence the expression of genes involved in lipoprotein metabolism in a tissue-selective manner in the rat.
      ,
      • Peters J.M.
      • Hennuyer N.
      • Staels B.
      • Fruchart J.C.
      • Fievet C.
      • Gonzalez F.J.
      • et al.
      Alterations in lipoprotein metabolism in peroxisome proliferator-activated receptor alpha-deficient mice.
      ]. In the human and mouse liver, APO-AII expression is induced by PPARα. Hepatic human APO-AII gene transcription is induced by PPARα through interaction with a PPRE localized within the APO-AII promoter region. A functional PPRE could not be identified within the mouse Apo-AII promoter [
      • Vu-Dac N.
      • Schoonjans K.
      • Kosykh V.
      • Dallongeville J.
      • Fruchart J.C.
      • Staels B.
      • et al.
      Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor.
      ]. However, based on available data from genome-wide PPARα binding map, we inspected through promoter regions of hepatic mouse Apo-AII for the presence of PPARα ChIP-seq peaks [
      • Boergesen M.
      • Pedersen T.A.
      • Gross B.
      • van Heeringen S.J.
      • Hagenbeek D.
      • Bindesboll C.
      • et al.
      Genome-wide profiling of liver X receptor, retinoid X receptor, and peroxisome proliferator-activated receptor alpha in mouse liver reveals extensive sharing of binding sites.
      ] and identified a PPARα binding also in the mouse Apo-AII proximal promoter, 100 bp downstream of the transcription start site (our unpublished data). Similar species-specific transcriptional regulation modes are observed for APO-AV, which enhances LPL activity, by PPARα [
      • Fruchart-Najib J.
      • Bauge E.
      • Niculescu L.S.
      • Pham T.
      • Thomas B.
      • Rommens C.
      • et al.
      Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5.
      ,
      • Schaap F.G.
      • Rensen P.C.
      • Voshol P.J.
      • Vrins C.
      • van der Vliet H.N.
      • Chamuleau R.A.
      • et al.
      ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis.
      ]. Studies using human LPL transgenic/Apo-AV-deficient mice and human APO-AV transgenic/Lpl-deficient mice support the hypothesis that APO-AV reduces TG levels by trafficking VLDL and chylomicrons to proteoglycan-bound LPL for lipolysis [
      • Merkel M.
      • Loeffler B.
      • Kluger M.
      • Fabig N.
      • Geppert G.
      • Pennacchio L.A.
      • et al.
      Apolipoprotein AV accelerates plasma hydrolysis of triglyceride-rich lipoproteins by interaction with proteoglycan-bound lipoprotein lipase.
      ,
      • Pennacchio L.A.
      • Olivier M.
      • Hubacek J.A.
      • Cohen J.C.
      • Cox D.R.
      • Fruchart J.C.
      • et al.
      An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.
      ]. In vitro and in vivo studies comparing wild-type versus transgenic humanized APO-AV mice revealed that human, but not mouse APO-AV expression is induced in the liver by PPARα agonists [
      • Prieur X.
      • Lesnik P.
      • Moreau M.
      • Rodriguez J.C.
      • Doucet C.
      • Chapman M.J.
      • et al.
      Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha. Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice.
      ,
      • Vu-Dac N.
      • Gervois P.
      • Jakel H.
      • Nowak M.
      • Bauge E.
      • Dehondt H.
      • et al.
      Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor alpha activators.
      ]. These findings are consistent with the identification of a functional PPRE in the human, but not mouse Apo-AV promoter [
      • Prieur X.
      • Lesnik P.
      • Moreau M.
      • Rodriguez J.C.
      • Doucet C.
      • Chapman M.J.
      • et al.
      Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha. Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice.
      ,
      • Vu-Dac N.
      • Gervois P.
      • Jakel H.
      • Nowak M.
      • Bauge E.
      • Dehondt H.
      • et al.
      Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor alpha activators.
      ]. In humans, rare SNPs in the APO-AV promoter region are associated with paradoxical decreases in plasma HDL-C and APO-AI in response to fibrates, whereas SNPs within the APO-AV gene are associated with enhanced lipid response to fibrate and statin therapy [
      • Brautbar A.
      • Barbalic M.
      • Chen F.
      • Belmont J.
      • Virani S.S.
      • Scherer S.
      • et al.
      Rare APOA5 promoter variants associated with paradoxical HDL cholesterol decrease in response to fenofibric acid therapy.
      ,
      • Brautbar A.
      • Covarrubias D.
      • Belmont J.
      • Lara-Garduno F.
      • Virani S.S.
      • Jones P.H.
      • et al.
      Variants in the APOA5 gene region and the response to combination therapy with statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia.
      ,
      • Lai C.Q.
      • Arnett D.K.
      • Corella D.
      • Straka R.J.
      • Tsai M.Y.
      • Peacock J.M.
      • et al.
      Fenofibrate effect on triglyceride and postprandial response of apolipoprotein A5 variants: the GOLDN study.
      ,
      • Cardona F.
      • Guardiola M.
      • Queipo-Ortuno M.I.
      • Murri M.
      • Ribalta J.
      • Tinahones F.J.
      The −1131T>C SNP of the APOA5 gene modulates response to fenofibrate treatment in patients with the metabolic syndrome: a postprandial study.
      ]. Thus, unexpected responses to fibrate treatment in some individuals may be due to genetic variations in PPARα target genes, such as APO-AV.

      Hepatic PPARα activity switches in the fed-to-fasted transition states

      PPARα coordinates different pathways of de novo lipid synthesis in the fed state, to supply FA for storage as hepatic TG, for periods of starvation. During fasting, when the organism switches to the utilization of FA, deriving either from the liver or from peripheral tissues, PPARα also shifts its activity to promote FA uptake and β-oxidation, thus yielding substrates for ketone body synthesis to provide energy for peripheral tissues (Fig. 2). The adjustment of PPARα transcriptional activity in the adaptation to fasting/feeding transition can be potentially brought about by kinases controlled by different nutritional states and phosphorylating PPARα or its regulatory proteins.
      Figure thumbnail gr2
      Fig. 2Molecular switch of PPARα activity in the fed-to-fasted state. Augmented postprandial glucose levels lead to increased production and secretion of insulin by β-cells, which acts on the liver to induce glucose uptake and glycolysis, yielding acetyl-CoA (AcCoA), and enhances FA synthesis. Insulin stimulates PPARα phosphorylation via PKC and enhances its transcriptional activity, whereas insulin-activated mTORC1 blocks PPARα activity by promoting nuclear localization of NCoR. Lipogenesis yields fatty acid-derivatives operating as PPARα ligands. During fasting, stress hormones such as adrenaline and glucocorticoids are synthesized together with glucagon. Glucagon sustains gluconeogenesis through a stimulatory effect on hepatic gluconeogenic precursor uptake as well as on the efficiency of gluconeogenesis within the liver. Moreover, glucagon increases cAMP levels triggering PKA-dependent PPARα phosphorylation and activity. Fasting leads to decreased mTOR1C activation and stimulation of PPARα-dependent FAO and ketogenesis. The lipolytic release of adipose tissue fatty acids raises plasma levels of free fatty acids (FFA) that are subsequently stored in the liver as TG. ATGL-dependent hydrolysis of hepatic intracellular TG provides lipid ligands for PPARα activation. PPARα activation leads to increased β-oxidation rates directly and via FGF21 activation to provide substrates for ketone body synthesis and gluconeogenesis, thus maintaining energy sources for peripheral tissues. During prolonged fasting, high intracellular AMP levels induce AMPK to stimulate energy production by PPARα-driven FAO.
      Several kinases, including PKA, PKC, and MAPK, have been shown to modify PPARα transcriptional activity (see also Table 1), although many studies were performed in vitro, and thus lack physiological translation to the coordinated responses to different nutritional signals in the living organism. However, insulin-activated MAPK and glucose-activated PKC stimulate PPARα transactivation in HepG2 cells [
      • Blanquart C.
      • Mansouri R.
      • Paumelle R.
      • Fruchart J.C.
      • Staels B.
      • Glineur C.
      The protein kinase C signaling pathway regulates a molecular switch between transactivation and transrepression activity of the peroxisome proliferator-activated receptor alpha.
      ,
      • Juge-Aubry C.E.
      • Hammar E.
      • Siegrist-Kaiser C.
      • Pernin A.
      • Takeshita A.
      • Chin W.W.
      • et al.
      Regulation of the transcriptional activity of the peroxisome proliferator-activated receptor alpha by phosphorylation of a ligand-independent trans-activating domain.
      ], suggesting that MAPK- and PKC-dependent phosphorylations may promote PPARα activity in the post-prandial state. Conversely, in fasting, glucagon induces cAMP and cAMP-dependent kinase PKA activity [
      • Jiang Y.
      • Cypess A.M.
      • Muse E.D.
      • Wu C.R.
      • Unson C.G.
      • Merrifield R.B.
      • et al.
      Glucagon receptor activates extracellular signal-regulated protein kinase 1/2 via cAMP-dependent protein kinase.
      ]. PKA-mediated phosphorylation potentiates ligand-dependent PPARα activation and increases expression of FAO genes in mouse primary hepatocytes [
      • Lazennec G.
      • Canaple L.
      • Saugy D.
      • Wahli W.
      Activation of peroxisome proliferator-activated receptors (PPARs) by their ligands and protein kinase A activators.
      ].
      Studies performed in mice hint that mTORC1 also plays a role in switching PPARα activities during the feeding/fasting transition as well as in pathophysiological conditions. In the fed state, when mTORC1 is activated by the insulin-dependent PI3K pathway, NCoR1 is partitionned in the cytoplasm and the nucleus of hepatocytes, thus repressing PPARα target gene expression [
      • Sengupta S.
      • Peterson T.R.
      • Laplante M.
      • Oh S.
      • Sabatini D.M.
      MTORC1 controls fasting-induced ketogenesis and its modulation by ageing.
      ]. Inhibition of mTORC1 and its downstream effector S6K2 during fasting promotes a cytoplasmic relocalization of NCoR1, hence increasing ketogenesis via PPARα derepression [
      • Sengupta S.
      • Peterson T.R.
      • Laplante M.
      • Oh S.
      • Sabatini D.M.
      MTORC1 controls fasting-induced ketogenesis and its modulation by ageing.
      ,
      • Kim K.
      • Pyo S.
      • Um S.H.
      S6 kinase 2 deficiency enhances ketone body production and increases peroxisome proliferator-activated receptor alpha activity in the liver.
      ]. Interestingly, S6K2 phosphorylation is elevated in ob/ob mice, a model of obesity and insulin resistance (IR) [
      • Kim K.
      • Pyo S.
      • Um S.H.
      S6 kinase 2 deficiency enhances ketone body production and increases peroxisome proliferator-activated receptor alpha activity in the liver.
      ]. The ability of FAS to synthesize phospholipids, acting as endogenous PPARα ligands, depends on its subcellular localization and post-translational modifications [
      • Jensen-Urstad A.P.
      • Song H.
      • Lodhi I.J.
      • Funai K.
      • Yin L.
      • Coleman T.
      • et al.
      Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARalpha.
      ]. Insulin-dependent phosphorylation of cytoplasmic FAS by mTORC1 limits PPARα ligand generation, whereas membrane-associated FAS, producing lipids for energy storage and export, is less susceptible to phosphorylation. Conversely, in the fasting state, de-phosphorylated cytoplasmic FAS is in a permissive state, allowing the generation of endogenous PPARα ligands, thus activating PPARα-target genes [
      • Jensen-Urstad A.P.
      • Song H.
      • Lodhi I.J.
      • Funai K.
      • Yin L.
      • Coleman T.
      • et al.
      Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARalpha.
      ].
      Hepatic PPARα activity can also be stimulated by AMPK, a sensor of the intracellular energy state activated by high AMP-to-ATP ratios, i.e., during fasting [
      • Bronner M.
      • Hertz R.
      • Bar-Tana J.
      Kinase-independent transcriptional co-activation of peroxisome proliferator-activated receptor alpha by AMP-activated protein kinase.
      ]. In contrast, glucose represses PPARα gene expression via AMPK inactivation in pancreatic β-cells [
      • Joly E.
      • Roduit R.
      • Peyot M.L.
      • Habinowski S.A.
      • Ruderman N.B.
      • Witters L.A.
      • et al.
      Glucose represses PPARalpha gene expression via AMP-activated protein kinase but not via p38 mitogen-activated protein kinase in the pancreatic beta-cell.
      ,
      • Ravnskjaer K.
      • Boergesen M.
      • Dalgaard L.T.
      • Mandrup S.
      Glucose-induced repression of PPARalpha gene expression in pancreatic beta-cells involves PP2A activation and AMPK inactivation.
      ], although it is unknown whether a similar mechanism occurs in the liver. Adiponectin, an insulin-sensitizing adipokine, increases FAO gene expression via AMPK-dependent PPARα activation [
      • Yoon M.J.
      • Lee G.Y.
      • Chung J.J.
      • Ahn Y.H.
      • Hong S.H.
      • Kim J.B.
      Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha.
      ]. Serum adiponectin is decreased in obesity and T2DM [
      • Hotta K.
      • Funahashi T.
      • Arita Y.
      • Takahashi M.
      • Matsuda M.
      • Okamoto Y.
      • et al.
      Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.
      ], which may contribute to an impaired PPARα activity in these pathologies.

      PPARα in acute and chronic liver inflammation

      PPARα and acute hepatic inflammation

      PPARα exerts anti-inflammatory activities in murine models of systemic inflammation. PPARα agonism specifically attenuates the IL-6-induced APR in vitro and in vivo, by downregulating hepatic expression levels of Saa, Hg, and Fib-α, -β and -γ [
      • Gervois P.
      • Kleemann R.
      • Pilon A.
      • Percevault F.
      • Koenig W.
      • Staels B.
      • et al.
      Global suppression of IL-6-induced acute phase response gene expression after chronic in vivo treatment with the peroxisome proliferator-activated receptor-alpha activator fenofibrate.
      ]. Similar inhibitory effects of PPARα agonists on IL-1β- and IL-6-induced APR were observed in mice with liver-restricted Pparα expression [
      • Mansouri R.M.
      • Bauge E.
      • Staels B.
      • Gervois P.
      Systemic and distal repercussions of liver-specific peroxisome proliferator-activated receptor-alpha control of the acute-phase response.
      ]. By contrast, treatment with IL-1β decreases expression of liver PPARα and its target genes, suggesting a negative crosstalk between IL-1β-induced inflammation and hepatic FAO regulation [
      • Stienstra R.
      • Saudale F.
      • Duval C.
      • Keshtkar S.
      • Groener J.E.
      • van Rooijen N.
      • et al.
      Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity.
      ]. In line with these observations, LPS-induced APR is counteracted by fibrates in Pparα-deficient mice with liver-specific reconstituted Pparα [
      • Mansouri R.M.
      • Bauge E.
      • Staels B.
      • Gervois P.
      Systemic and distal repercussions of liver-specific peroxisome proliferator-activated receptor-alpha control of the acute-phase response.
      ]. Interestingly, pretreatment with a PPARα agonist markedly prevents the LPS-induced increase of plasma IL-1, IL-6, and TNF, and the expression of adhesion molecules, such as ICAM-1 and VCAM-1 in the aorta, suggesting that liver PPARα controls, in a yet undefined manner, the systemic inflammatory response [
      • Mansouri R.M.
      • Bauge E.
      • Staels B.
      • Gervois P.
      Systemic and distal repercussions of liver-specific peroxisome proliferator-activated receptor-alpha control of the acute-phase response.
      ]. The anti-inflammatory effects of hepatic PPARα may also derive from its ability to upregulate anti-inflammatory genes, such as Il-1ra and IκBα, a cytoplasmic inhibitor of NFκB, suggesting a possible cooperation between PPARα-dependent transactivation and transrepression to turn on anti-inflammatory pathways [
      • Stienstra R.
      • Mandard S.
      • Tan N.S.
      • Wahli W.
      • Trautwein C.
      • Richardson T.A.
      • et al.
      The Interleukin-1 receptor antagonist is a direct target gene of PPARalpha in liver.
      ,
      • Kleemann R.
      • Gervois P.P.
      • Verschuren L.
      • Staels B.
      • Princen H.M.
      • Kooistra T.
      Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFkappa B-C/EBP-beta complex formation.
      ].

      PPARα action in pre-clinical models of NAFLD

      NAFLD is a chronic liver disease, which affects 10–24% of the population and is associated with IR and the MetS [
      • Allard J.P.
      • Aghdassi E.
      • Mohammed S.
      • Raman M.
      • Avand G.
      • Arendt B.M.
      • et al.
      Nutritional assessment and hepatic fatty acid composition in non-alcoholic fatty liver disease (NAFLD): a cross-sectional study.
      ]. The pathology initiates with hepatic steatosis, which in some individuals progresses toward NASH, fibrosis, cirrhosis and finally liver failure. The ability of PPARα to counteract different stages of NAFLD has been studied in animal models, which partially replicate the human pathology [
      • Tailleux A.
      • Wouters K.
      • Staels B.
      Roles of PPARs in NAFLD: potential therapeutic targets.
      ].
      Administration of an methionine choline-deficient diet (MCDD) to rodents leads to the development of steatohepatitis, histologically similar to human NASH. However, MCDD does not induce peripheral IR, normally observed in human NASH. Pparα-deficiency in MCDD-fed mice provokes more severe steatosis and hepatitis [
      • Ip E.
      • Farrell G.C.
      • Robertson G.
      • Hall P.
      • Kirsch R.
      • Leclercq I.
      Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice.
      ]. In wild-type mice, PPARα agonism normalizes histological changes by preventing intrahepatic lipid accumulation, liver inflammation, and fibrosis [
      • Ip E.
      • Farrell G.
      • Hall P.
      • Robertson G.
      • Leclercq I.
      Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice.
      ]. Pharmacological activation of PPARα increases CYP4A-driven ω-oxidation as well as peroxisomal and mitochondrial β-oxidation, leading to enhanced hepatic lipid turnover. Moreover, synthetic PPARα agonists decrease the number of activated macrophages and stellate cells in the liver, and lower the expression of fibrotic markers [
      • Ip E.
      • Farrell G.C.
      • Robertson G.
      • Hall P.
      • Kirsch R.
      • Leclercq I.
      Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice.
      ]. In rodents, PPARα appears to be expressed mainly in hepatocytes [
      • Peters J.M.
      • Rusyn I.
      • Rose M.L.
      • Gonzalez F.J.
      • Thurman R.G.
      Peroxisome proliferator-activated receptor alpha is restricted to hepatic parenchymal cells, not Kupffer cells: implications for the mechanism of action of peroxisome proliferators in hepatocarcinogenesis.
      ], suggesting that the hepatoprotective effects of fibrates in rodents likely occur via PPARα within liver parenchymal cells (Fig. 3). We showed that the hepato-specific expression of the DNA-binding disabled PPARαDISS protects from MCDD-induced inflammation and liver fibrosis, without affecting FAO genes and lipid accumulation in the liver [
      • Pawlak M.
      • Bauge E.
      • Bourguet W.
      • De Bosscher K.
      • Lalloyer F.
      • Tailleux A.
      • et al.
      The transrepressive activity of Pparalpha is necessary and sufficient to prevent liver fibrosis.
      ]. Hepatoprotective effects of PPARα agonism can also occur via the regulation of hepatic Vnn1 expression [
      • Rommelaere S.
      • Millet V.
      • Gensollen T.
      • Bourges C.
      • Eeckhoute J.
      • Hennuyer N.
      • et al.
      PPARalpha regulates the production of serum Vanin-1 by liver.
      ], since Vnn1-deficiency links hepatic steatosis in response to fasting and changes the expression of inflammation and oxidative stress genes [
      • van Diepen J.A.
      • Jansen P.A.
      • Ballak D.B.
      • Hijmans A.
      • Hooiveld G.J.
      • Rommelaere S.
      • et al.
      PPAR-alpha dependent regulation of vanin-1 mediates hepatic lipid metabolism.
      ]. The role of ATGL-dependent intracellular TG hydrolysis, to generate endogenous PPARα agonists with anti-inflammatory potential, was recently demonstrated in Atgl-deficient mice [
      • Jha P.
      • Claudel T.
      • Baghdasaryan A.
      • Mueller M.
      • Halilbasic E.
      • Das S.K.
      • et al.
      Role of adipose triglyceride lipase (PNPLA2) in protection from hepatic inflammation in mouse models of steatohepatitis and endotoxemia.
      ], which display increased susceptibility to LPS- and MCDD-induced hepatic inflammation due to impaired PPARα signaling. The hepatic phenotype of Atlg-deficient mice is partially improved upon treatment with a synthetic PPARα agonist. The foz/foz (ALMS1 mutant) mouse model of Alström syndrome spontaneously exhibits a strong metabolic phenotype hallmarked by severe obesity, hyperinsulinemia and T2DM [
      • Arsov T.
      • Silva D.G.
      • O’Bryan M.K.
      • Sainsbury A.
      • Lee N.J.
      • Kennedy C.
      • et al.
      Fat aussie–a new Alstrom syndrome mouse showing a critical role for ALMS1 in obesity, diabetes, and spermatogenesis.
      ,
      • Larter C.Z.
      • Yeh M.M.
      • Van Rooyen D.M.
      • Teoh N.C.
      • Brooling J.
      • Hou J.Y.
      • et al.
      Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice.
      ,
      • Collin G.B.
      • Cyr E.
      • Bronson R.
      • Marshall J.D.
      • Gifford E.J.
      • Hicks W.
      • et al.
      Alms1-disrupted mice recapitulate human Alstrom syndrome.
      ]. In this genetic background, PPARα activation reverses HFD-induced hepatocellular injury, liver inflammation and improves insulin sensitivity [
      • Larter C.Z.
      • Yeh M.M.
      • Van Rooyen D.M.
      • Brooling J.
      • Ghatora K.
      • Farrell G.C.
      Peroxisome proliferator-activated receptor-alpha agonist, Wy 14,643, improves metabolic indices, steatosis and ballooning in diabetic mice with non-alcoholic steatohepatitis.
      ]. Similarly, Pparα-deficiency promotes HFD-induced hepatic TG, macrophage infiltration and elevates plasma levels of ALT and SAA [
      • Abdelmegeed M.A.
      • Yoo S.H.
      • Henderson L.E.
      • Gonzalez F.J.
      • Woodcroft K.J.
      • Song B.J.
      PPARalpha expression protects male mice from high fat-induced nonalcoholic fatty liver.
      ]. In contrast to the observation that PPARα activation improves insulin sensitivity [
      • Guerre-Millo M.
      • Gervois P.
      • Raspe E.
      • Madsen L.
      • Poulain P.
      • Derudas B.
      • et al.
      Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity.
      ], Pparα-deficient mice are protected from HFD-induced IR, as assessed by glucose tolerance test and euglycemic-hyperinsulinemic clamps in fasted mice [
      • Guerre-Millo M.
      • Gervois P.
      • Raspe E.
      • Madsen L.
      • Poulain P.
      • Derudas B.
      • et al.
      Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity.
      ,
      • Tordjman K.
      • Bernal-Mizrachi C.
      • Zemany L.
      • Weng S.
      • Feng C.
      • Zhang F.
      • et al.
      PPARalpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice.
      ]. Similar tests performed in non-fasted Pparα-deficient mice, however, show no protection from IR compared to wild-type mice [
      • Haluzik M.
      • Gavrilova O.
      • LeRoith D.
      Peroxisome proliferator-activated receptor-alpha deficiency does not alter insulin sensitivity in mice maintained on regular or high-fat diet: hyperinsulinemic-euglycemic clamp studies.
      ]. These contradictions can result from the impaired response to fasting in Pparα-deficient mice, in which the inability to oxidize FA leads to a preferential glucose use and depletion of glycogen stores [
      • Haluzik M.M.
      • Haluzik M.
      PPAR-alpha and insulin sensitivity.
      ].
      Figure thumbnail gr3
      Fig. 3Hepatoprotective effects of fibrates: examples from rodent models of NAFLD. Development of NASH is provoked by different risk factors, such as Western-type diet, physical inactivity and genetic predispositions that often lead to insulin resistance and T2DM. Exaggerated food intake leads to FA synthesis via hepatic lipogenesis pathways. Enhanced TG storage in the liver (steatosis) provokes uncontrolled lipid peroxidation that generates reactive oxygen species (ROS) and cytotoxic aldehydes. Hepatocyte damage leads to increased inflammatory signaling (IL-1, TNF), acute phase response (APR) and recruitment of circulating (Mφ) and residual macrophages (KC). All of these mechanisms can directly induce apoptosis, necrosis and TGFβ-dependent activation of hepatic stellate cells (HSC) that are the main source of extracellular matrix protein in liver, thus contributing in fibrosis progression. In several mouse models of NAFLD, fibrate-activated PPARα counteracts different stages of NAFLD by promoting FAO and hampering pro-inflammatory response. Moreover, fibrate treatment induces catalase (CAT) expression thus diminishing H2O2 levels in the liver. Hepatic cirrhosis is associated with endothelial dysfunction and impaired intrahepatic hemodynamics that may lead to liver failure. Fibrates improve and ameliorate hepatic vascular resistance by reducing cyclo-oxygenase-1 (COX-1) protein expression.
      The development of early stages of NASH was studied in the humanized APO-E2 knock-in (APO-E2KI) mouse. In this model, the Apo-E gene has been substituted for the human APOE2 allele under the control of the endogenous mouse promoter, faithfully mimicking mouse endogenous APO-E tissue distribution and expression levels. The reduced affinity of hAPO-E2 for the LDL-receptor leads to a plasma lipoprotein profile similar to that occurring in human type III hyperlipoproteinemia [
      • Tailleux A.
      • Wouters K.
      • Staels B.
      Roles of PPARs in NAFLD: potential therapeutic targets.
      ]. APO-E2-KI mice fed a western diet rapidly develop a phenotype characterized by steatosis and inflammation. Interestingly, macrophage infiltration in the liver precedes lipid accumulation. This is in contradiction with the concept that NASH pathogenesis always stems from initial liver steatosis, which leads to inflammation [
      • Shiri-Sverdlov R.
      • Wouters K.
      • van Gorp P.J.
      • Gijbels M.J.
      • Noel B.
      • Buffat L.
      • et al.
      Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates.
      ]. In accordance, clodronate liposome-induced depletion of residual liver macrophages (Kupffer cells) reduces hepatic TG content in HFD-fed wild-type mice [
      • Stienstra R.
      • Saudale F.
      • Duval C.
      • Keshtkar S.
      • Groener J.E.
      • van Rooijen N.
      • et al.
      Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity.
      ]. Western diet-fed Pparα-deficient/APO-E2-KI mice manifest exacerbated liver steatosis and inflammation compared to wild-type APO-E2-KI mice, indicative of a protective role of PPARα against NASH [
      • Lalloyer F.
      • Wouters K.
      • Baron M.
      • Caron S.
      • Vallez E.
      • Vanhoutte J.
      • et al.
      Peroxisome proliferator-activated receptor-alpha gene level differently affects lipid metabolism and inflammation in apolipoprotein E2 knock-in mice.
      ]. Consistently, in primary hepatocytes isolated from APO-E2-KI mice, HFD induces an aberrant histone H3K9me3 and H3K4me3 methylation profile of the promoter of Pparα, which correlates with decreased Pparα mRNA expression [
      • Jun H.J.
      • Kim J.
      • Hoang M.H.
      • Lee S.J.
      Hepatic lipid accumulation alters global histone h3 lysine 9 and 4 trimethylation in the peroxisome proliferator-activated receptor alpha network.
      ]. In APO-E2-KI mice expressing PPARα, fibrates inhibit NASH due to their inhibitory effects on pro-inflammatory genes and the increase in lipid catabolism in the liver [
      • Shiri-Sverdlov R.
      • Wouters K.
      • van Gorp P.J.
      • Gijbels M.J.
      • Noel B.
      • Buffat L.
      • et al.
      Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates.
      ,
      • Lalloyer F.
      • Wouters K.
      • Baron M.
      • Caron S.
      • Vallez E.
      • Vanhoutte J.
      • et al.
      Peroxisome proliferator-activated receptor-alpha gene level differently affects lipid metabolism and inflammation in apolipoprotein E2 knock-in mice.
      ]. Among the ROS, hydrogen peroxide is a major agent activating TGFβ and collagen production by hepatic stellate cells [
      • Svegliati Baroni G.
      • D’Ambrosio L.
      • Ferretti G.
      • Casini A.
      • Di Sario A.
      • Salzano R.
      • et al.
      Fibrogenic effect of oxidative stress on rat hepatic stellate cells.
      ,
      • De Bleser P.J.
      • Xu G.
      • Rombouts K.
      • Rogiers V.
      • Geerts A.
      Glutathione levels discriminate between oxidative stress and transforming growth factor-beta signaling in activated rat hepatic stellate cells.
      ]. The anti-fibrotic action of synthetic PPARα agonists was demonstrated in a rat model of thioacetamide-induced liver cirrhosis. PPARα directly upregulates catalase expression, thus ameliorating hydrogen peroxide detoxification and protecting hepatocytes from oxidative stress [
      • Toyama T.
      • Nakamura H.
      • Harano Y.
      • Yamauchi N.
      • Morita A.
      • Kirishima T.
      • et al.
      PPARalpha ligands activate antioxidant enzymes and suppress hepatic fibrosis in rats.
      ]. Moreover, fibrates improve endothelial dysfunction and ameliorate intrahepatic hemodynamics in CCl4 cirrhotic rats, at least in part, by reducing COX-1 protein expression [
      • Rodriguez-Vilarrupla A.
      • Lavina B.
      • Garcia-Caldero H.
      • Russo L.
      • Rosado E.
      • Roglans N.
      • et al.
      PPARalpha activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats.
      ].

      Perspectives

      Genome-wide approaches have shown that PPARα is a master regulator of FA metabolism and ketogenesis in the liver [
      • Rakhshandehroo M.
      • Hooiveld G.
      • Muller M.
      • Kersten S.
      Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human.
      ]. The ability of PPARα agonists to counteract steatohepatitis and fibrosis appears prominent in murine models of NAFLD, which can be explained by the fact that PPARα expression is more abundant in the mouse compared to human liver and may further decrease with NASH progression (our unpublished data). Moreover, commonly used fibrates are relatively low activators of human PPARα. Thus potent and highly specific PPARα agonists, such as K-877 and the dual PPARα/δ agonist GFT505, have appeared as promising therapies for CVD or NAFLD, respectively. Nevertheless, further clinical studies are required to determine the effectiveness and safety of such SPPARMs in humans. Since the anti-inflammatory and anti-fibrotic activities of PPARα seem to be dissociable from its effect on liver steatosis in mice [
      • Pawlak M.
      • Bauge E.
      • Bourguet W.
      • De Bosscher K.
      • Lalloyer F.
      • Tailleux A.
      • et al.
      The transrepressive activity of Pparalpha is necessary and sufficient to prevent liver fibrosis.
      ], more potent, possibly selective transrepression-triggering PPARα agonists could be designed in the future, based on virtual drug screening and transcriptomics. A better understanding of PPARα regulation by different nutritional signals in healthy individuals and in MetS patients will allow the design of specific pharmacological therapies, simultaneously targeting different NASH-triggering factors. Moreover, to improve NASH, dietary strategies, such as n-3 PUFA supplementation may be considered to ameliorate steatosis and inflammation, by a mechanism that may partially rely on PPARα activation [
      • Parker H.M.
      • Johnson N.A.
      • Burdon C.A.
      • Cohn J.S.
      • O’Connor H.T.
      • George J.
      Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis.
      ,
      • Lu Y.
      • Boekschoten M.V.
      • Wopereis S.
      • Muller M.
      • Kersten S.
      Comparative transcriptomic and metabolomic analysis of fenofibrate and fish oil treatments in mice.
      ]. However, the efficacy of n-3 PUFA in the treatment of NASH in human subjects remains to be demonstrated.

      Conflict of interest

      BS is an advisor of Genfit SA.

      References

        • Issemann I.
        • Green S.
        Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators.
        Nature. 1990; 347: 645-650
        • Kliewer S.A.
        • Forman B.M.
        • Blumberg B.
        • Ong E.S.
        • Borgmeyer U.
        • Mangelsdorf D.J.
        • et al.
        Differential expression and activation of a family of murine peroxisome proliferator-activated receptors.
        Proc Natl Acad Sci U S A. 1994; 91: 7355-7359
        • Lefebvre P.
        • Chinetti G.
        • Fruchart J.C.
        • Staels B.
        Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis.
        J Clin Invest. 2006; 116: 571-580
        • Hashimoto T.
        • Cook W.S.
        • Qi C.
        • Yeldandi A.V.
        • Reddy J.K.
        • Rao M.S.
        Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting.
        J Biol Chem. 2000; 275: 28918-28928
        • Xu J.
        • Xiao G.
        • Trujillo C.
        • Chang V.
        • Blanco L.
        • Joseph S.B.
        • et al.
        Peroxisome proliferator-activated receptor alpha (PPARalpha) influences substrate utilization for hepatic glucose production.
        J Biol Chem. 2002; 277: 50237-50244
        • Gervois P.
        • Kleemann R.
        • Pilon A.
        • Percevault F.
        • Koenig W.
        • Staels B.
        • et al.
        Global suppression of IL-6-induced acute phase response gene expression after chronic in vivo treatment with the peroxisome proliferator-activated receptor-alpha activator fenofibrate.
        J Biol Chem. 2004; 279: 16154-16160
        • Ip E.
        • Farrell G.C.
        • Robertson G.
        • Hall P.
        • Kirsch R.
        • Leclercq I.
        Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice.
        Hepatology. 2003; 38: 123-132
        • Staels B.
        • Maes M.
        • Zambon A.
        Fibrates and future PPARalpha agonists in the treatment of cardiovascular disease.
        Nat Clin Pract Cardiovasc Med. 2008; 5: 542-553
        • Staels B.
        • Rubenstrunk A.
        • Noel B.
        • Rigou G.
        • Delataille P.
        • Millatt L.J.
        • et al.
        Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
        Hepatology. 2013; 58: 1941-1952
        • Gearing K.L.
        • Crickmore A.
        • Gustafsson J.A.
        Structure of the mouse peroxisome proliferator activated receptor alpha gene.
        Biochem Biophys Res Commun. 1994; 199: 255-263
        • Barger P.M.
        • Browning A.C.
        • Garner A.N.
        • Kelly D.P.
        P38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: a potential role in the cardiac metabolic stress response.
        J Biol Chem. 2001; 276: 44495-44501
        • Hummasti S.
        • Tontonoz P.
        The peroxisome proliferator-activated receptor N-terminal domain controls isotype-selective gene expression and adipogenesis.
        Mol Endocrinol. 2006; 20: 1261-1275
        • Gearing K.L.
        • Gottlicher M.
        • Teboul M.
        • Widmark E.
        • Gustafsson J.A.
        Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor.
        Proc Natl Acad Sci U S A. 1993; 90: 1440-1444
        • Juge-Aubry C.
        • Pernin A.
        • Favez T.
        • Burger A.G.
        • Wahli W.
        • Meier C.A.
        • et al.
        DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance of the 5′-flanking region.
        J Biol Chem. 1997; 272: 25252-25259
        • Dowell P.
        • Ishmael J.E.
        • Avram D.
        • Peterson V.J.
        • Nevrivy D.J.
        • Leid M.
        Identification of nuclear receptor corepressor as a peroxisome proliferator-activated receptor alpha interacting protein.
        J Biol Chem. 1999; 274: 15901-15907
        • Blanquart C.
        • Mansouri R.
        • Paumelle R.
        • Fruchart J.C.
        • Staels B.
        • Glineur C.
        The protein kinase C signaling pathway regulates a molecular switch between transactivation and transrepression activity of the peroxisome proliferator-activated receptor alpha.
        Mol Endocrinol. 2004; 18: 1906-1918
        • Pourcet B.
        • Pineda-Torra I.
        • Derudas B.
        • Staels B.
        • Glineur C.
        SUMOylation of human peroxisome proliferator-activated receptor alpha inhibits its trans-activity through the recruitment of the nuclear corepressor NCoR.
        J Biol Chem. 2010; 285: 5983-5992
        • Xu H.E.
        • Lambert M.H.
        • Montana V.G.
        • Plunket K.D.
        • Moore L.B.
        • Collins J.L.
        • et al.
        Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors.
        Proc Natl Acad Sci U S A. 2001; 98: 13919-13924
        • Gampe Jr., R.T.
        • Montana V.G.
        • Lambert M.H.
        • Miller A.B.
        • Bledsoe R.K.
        • Milburn M.V.
        • et al.
        Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors.
        Mol Cell. 2000; 5: 545-555
        • Batista F.A.
        • Trivella D.B.
        • Bernardes A.
        • Gratieri J.
        • Oliveira P.S.
        • Figueira A.C.
        • et al.
        Structural insights into human peroxisome proliferator activated receptor delta (PPAR-delta) selective ligand binding.
        PLoS One. 2012; 7: e33643
        • Cronet P.
        • Petersen J.F.
        • Folmer R.
        • Blomberg N.
        • Sjoblom K.
        • Karlsson U.
        • et al.
        Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family.
        Structure. 2001; 9: 699-706
        • Leuenberger N.
        • Pradervand S.
        • Wahli W.
        Sumoylated PPARalpha mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice.
        J Clin Invest. 2009; 119: 3138-3148
        • Fan C.Y.
        • Pan J.
        • Chu R.
        • Lee D.
        • Kluckman K.D.
        • Usuda N.
        • et al.
        Hepatocellular and hepatic peroxisomal alterations in mice with a disrupted peroxisomal fatty acyl-coenzyme A oxidase gene.
        J Biol Chem. 1996; 271: 24698-24710
        • Fan C.Y.
        • Pan J.
        • Usuda N.
        • Yeldandi A.V.
        • Rao M.S.
        • Reddy J.K.
        Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase. Implications for peroxisome proliferator-activated receptor alpha natural ligand metabolism.
        J Biol Chem. 1998; 273: 15639-15645
        • Yu K.
        • Bayona W.
        • Kallen C.B.
        • Harding H.P.
        • Ravera C.P.
        • McMahon G.
        • et al.
        Differential activation of peroxisome proliferator-activated receptors by eicosanoids.
        J Biol Chem. 1995; 270: 23975-23983
        • Delerive P.
        • Furman C.
        • Teissier E.
        • Fruchart J.
        • Duriez P.
        • Staels B.
        Oxidized phospholipids activate PPARalpha in a phospholipase A2-dependent manner.
        FEBS Lett. 2000; 471: 34-38
        • Chakravarthy M.V.
        • Pan Z.
        • Zhu Y.
        • Tordjman K.
        • Schneider J.G.
        • Coleman T.
        • et al.
        “New” hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis.
        Cell Metab. 2005; 1: 309-322
        • Chakravarthy M.V.
        • Lodhi I.J.
        • Yin L.
        • Malapaka R.R.
        • Xu H.E.
        • Turk J.
        • et al.
        Identification of a physiologically relevant endogenous ligand for PPARalpha in liver.
        Cell. 2009; 138: 476-488
        • Sapiro J.M.
        • Mashek M.T.
        • Greenberg A.S.
        • Mashek D.G.
        Hepatic triacylglycerol hydrolysis regulates peroxisome proliferator-activated receptor alpha activity.
        J Lipid Res. 2009; 50: 1621-1629
        • Reid B.N.
        • Ables G.P.
        • Otlivanchik O.A.
        • Schoiswohl G.
        • Zechner R.
        • Blaner W.S.
        • et al.
        Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis.
        J Biol Chem. 2008; 283: 13087-13099
        • Fruchart J.C.
        Selective peroxisome proliferator-activated receptor alpha modulators (SPPARMalpha): the next generation of peroxisome proliferator-activated receptor alpha-agonists.
        Cardiovasc Diabetol. 2013; 12: 82
        • Willson T.M.
        • Brown P.J.
        • Sternbach D.D.
        • Henke B.R.
        The PPARs: from orphan receptors to drug discovery.
        J Med Chem. 2000; 43: 527-550
        • Cariou B.
        • Staels B.
        GFT505 for the treatment of nonalcoholic steatohepatitis and type 2 diabetes.
        Expert Opin Investig Drugs. 2014; 23: 1441-1448
        • Surapureddi S.
        • Yu S.
        • Bu H.
        • Hashimoto T.
        • Yeldandi A.V.
        • Kashireddy P.
        • et al.
        Identification of a transcriptionally active peroxisome proliferator-activated receptor alpha -interacting cofactor complex in rat liver and characterization of PRIC285 as a coactivator.
        Proc Natl Acad Sci U S A. 2002; 99: 11836-11841
        • Pawlak M.
        • Bauge E.
        • Bourguet W.
        • De Bosscher K.
        • Lalloyer F.
        • Tailleux A.
        • et al.
        The transrepressive activity of Pparalpha is necessary and sufficient to prevent liver fibrosis.
        Hepatology. 2014; 60: 1593-1606
        • Jia Y.
        • Qi C.
        • Kashireddi P.
        • Surapureddi S.
        • Zhu Y.J.
        • Rao M.S.
        • et al.
        Transcription coactivator PBP, the peroxisome proliferator-activated receptor (PPAR)-binding protein, is required for PPARalpha-regulated gene expression in liver.
        J Biol Chem. 2004; 279: 24427-24434
        • IJpenberg A.
        • Tan N.S.
        • Gelman L.
        • Kersten S.
        • Seydoux J.
        • Xu J.
        • et al.
        In vivo activation of PPAR target genes by RXR homodimers.
        EMBO J. 2004; 23: 2083-2091
        • Boergesen M.
        • Pedersen T.A.
        • Gross B.
        • van Heeringen S.J.
        • Hagenbeek D.
        • Bindesboll C.
        • et al.
        Genome-wide profiling of liver X receptor, retinoid X receptor, and peroxisome proliferator-activated receptor alpha in mouse liver reveals extensive sharing of binding sites.
        Mol Cell Biol. 2012; 32: 852-867
        • van der Meer D.L.
        • Degenhardt T.
        • Vaisanen S.
        • de Groot P.J.
        • Heinaniemi M.
        • de Vries S.C.
        • et al.
        Profiling of promoter occupancy by PPARalpha in human hepatoma cells via ChIP-chip analysis.
        Nucleic Acids Res. 2010; 38: 2839-2850
        • McMullen P.D.
        • Bhattacharya S.
        • Woods C.G.
        • Sun B.
        • Yarborough K.
        • Ross S.M.
        • et al.
        A map of the PPARalpha transcription regulatory network for primary human hepatocytes.
        Chem Biol Interact. 2014; 209: 14-24
        • Rakhshandehroo M.
        • Hooiveld G.
        • Muller M.
        • Kersten S.
        Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human.
        PLoS One. 2009; 4: e6796
        • Rakhshandehroo M.
        • Sanderson L.M.
        • Matilainen M.
        • Stienstra R.
        • Carlberg C.
        • de Groot P.J.
        • et al.
        Comprehensive analysis of PPARalpha-dependent regulation of hepatic lipid metabolism by expression profiling.
        PPAR Res. 2007; 2007: 26839
        • Delerive P.
        • De Bosscher K.
        • Besnard S.
        • Vanden Berghe W.
        • Peters J.M.
        • Gonzalez F.J.
        • et al.
        Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1.
        J Biol Chem. 1999; 274: 32048-32054
        • Bougarne N.
        • Paumelle R.
        • Caron S.
        • Hennuyer N.
        • Mansouri R.
        • Gervois P.
        • et al.
        PPARalpha blocks glucocorticoid receptor alpha-mediated transactivation but cooperates with the activated glucocorticoid receptor alpha for transrepression on NF-kappaB.
        Proc Natl Acad Sci U S A. 2009; 106: 7397-7402
        • Xu X.
        • Otsuki M.
        • Saito H.
        • Sumitani S.
        • Yamamoto H.
        • Asanuma N.
        • et al.
        PPARalpha and GR differentially down-regulate the expression of nuclear factor-kappaB-responsive genes in vascular endothelial cells.
        Endocrinology. 2001; 142: 3332-3339
        • Gervois P.
        • Vu-Dac N.
        • Kleemann R.
        • Kockx M.
        • Dubois G.
        • Laine B.
        • et al.
        Negative regulation of human fibrinogen gene expression by peroxisome proliferator-activated receptor alpha agonists via inhibition of CCAAT box/enhancer-binding protein beta.
        J Biol Chem. 2001; 276: 33471-33477
        • Oka S.
        • Alcendor R.
        • Zhai P.
        • Park J.Y.
        • Shao D.
        • Cho J.
        • et al.
        PPARalpha-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway.
        Cell Metab. 2011; 14: 598-611
        • Oka S.
        • Zhai P.
        • Alcendor R.
        • Park J.Y.
        • Tian B.
        • Sadoshima J.
        Suppression of ERR targets by a PPARalpha/Sirt1 complex in the failing heart.
        Cell Cycle. 2012; 11: 856-864
        • Mogilenko D.A.
        • Kudriavtsev I.V.
        • Shavva V.S.
        • Dizhe E.B.
        • Vilenskaya E.G.
        • Efremov A.M.
        • et al.
        Peroxisome proliferator-activated receptor alpha positively regulates complement C3 expression but inhibits tumor necrosis factor alpha-mediated activation of C3 gene in mammalian hepatic-derived cells.
        J Biol Chem. 2013; 288: 1726-1738
        • Schaffer J.E.
        • Lodish H.F.
        Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein.
        Cell. 1994; 79: 427-436
        • Martin G.
        • Schoonjans K.
        • Lefebvre A.M.
        • Staels B.
        • Auwerx J.
        Coordinate regulation of the expression of the fatty acid transport protein and acyl-CoA synthetase genes by PPARalpha and PPARgamma activators.
        J Biol Chem. 1997; 272: 28210-28217
        • Frohnert B.I.
        • Hui T.Y.
        • Bernlohr D.A.
        Identification of a functional peroxisome proliferator-responsive element in the murine fatty acid transport protein gene.
        J Biol Chem. 1999; 274: 3970-3977
        • Motojima K.
        • Passilly P.
        • Peters J.M.
        • Gonzalez F.J.
        • Latruffe N.
        Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner.
        J Biol Chem. 1998; 273: 16710-16714
        • Helledie T.
        • Grontved L.
        • Jensen S.S.
        • Kiilerich P.
        • Rietveld L.
        • Albrektsen T.
        • et al.
        The gene encoding the Acyl-CoA-binding protein is activated by peroxisome proliferator-activated receptor gamma through an intronic response element functionally conserved between humans and rodents.
        J Biol Chem. 2002; 277: 26821-26830
        • Hostetler H.A.
        • McIntosh A.L.
        • Atshaves B.P.
        • Storey S.M.
        • Payne H.R.
        • Kier A.B.
        • et al.
        L-FABP directly interacts with PPARalpha in cultured primary hepatocytes.
        J Lipid Res. 2009; 50: 1663-1675
        • Velkov T.
        Interactions between human liver fatty acid binding protein and peroxisome proliferator activated receptor selective drugs.
        PPAR Res. 2013; 2013: 938401
        • Wolfrum C.
        • Borrmann C.M.
        • Borchers T.
        • Spener F.
        Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha – and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus.
        Proc Natl Acad Sci U S A. 2001; 98: 2323-2328
        • Louet J.F.
        • Chatelain F.
        • Decaux J.F.
        • Park E.A.
        • Kohl C.
        • Pineau T.
        • et al.
        Long-chain fatty acids regulate liver carnitine palmitoyltransferase I gene (L-CPT I) expression through a peroxisome-proliferator-activated receptor alpha (PPARalpha)-independent pathway.
        Biochem J. 2001; 354: 189-197
        • Mascaro C.
        • Acosta E.
        • Ortiz J.A.
        • Marrero P.F.
        • Hegardt F.G.
        • Haro D.
        Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor.
        J Biol Chem. 1998; 273: 8560-8563
        • Barrero M.J.
        • Camarero N.
        • Marrero P.F.
        • Haro D.
        Control of human carnitine palmitoyltransferase II gene transcription by peroxisome proliferator-activated receptor through a partially conserved peroxisome proliferator-responsive element.
        Biochem J. 2003; 369: 721-729
        • Gulick T.
        • Cresci S.
        • Caira T.
        • Moore D.D.
        • Kelly D.P.
        The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression.
        Proc Natl Acad Sci U S A. 1994; 91: 11012-11016
        • Aoyama T.
        • Peters J.M.
        • Iritani N.
        • Nakajima T.
        • Furihata K.
        • Hashimoto T.
        • et al.
        Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha).
        J Biol Chem. 1998; 273: 5678-5684
        • Reddy J.K.
        • Azarnoff D.L.
        • Hignite C.E.
        Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens.
        Nature. 1980; 283: 397-398
        • Yu S.
        • Cao W.Q.
        • Kashireddy P.
        • Meyer K.
        • Jia Y.
        • Hughes D.E.
        • et al.
        Human peroxisome proliferator-activated receptor alpha (PPARalpha) supports the induction of peroxisome proliferation in PPARalpha-deficient mouse liver.
        J Biol Chem. 2001; 276: 42485-42491
        • Morimura K.
        • Cheung C.
        • Ward J.M.
        • Reddy J.K.
        • Gonzalez F.J.
        Differential susceptibility of mice humanized for peroxisome proliferator-activated receptor alpha to Wy-14,643-induced liver tumorigenesis.
        Carcinogenesis. 2006; 27: 1074-1080
        • Shah Y.M.
        • Morimura K.
        • Yang Q.
        • Tanabe T.
        • Takagi M.
        • Gonzalez F.J.
        Peroxisome proliferator-activated receptor alpha regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation.
        Mol Cell Biol. 2007; 27: 4238-4247
        • De La Iglesia F.A.
        • Lewis J.E.
        • Buchanan R.A.
        • Marcus E.L.
        • McMahon G.
        Light and electron microscopy of liver in hyperlipoproteinemic patients under long-term gemfibrozil treatment.
        Atherosclerosis. 1982; 43: 19-37
        • Blumcke S.
        • Schwartzkopff W.
        • Lobeck H.
        • Edmondson N.A.
        • Prentice D.E.
        • Blane G.F.
        Influence of fenofibrate on cellular and subcellular liver structure in hyperlipidemic patients.
        Atherosclerosis. 1983; 46: 105-116
        • Bonovas S.
        • Nikolopoulos G.K.
        • Bagos P.G.
        Use of fibrates and cancer risk: a systematic review and meta-analysis of 17 long-term randomized placebo-controlled trials.
        PLoS One. 2012; 7: e45259
        • Rodriguez J.C.
        • Gil-Gomez G.
        • Hegardt F.G.
        • Haro D.
        Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids.
        J Biol Chem. 1994; 269: 18767-18772
        • Kersten S.
        • Seydoux J.
        • Peters J.M.
        • Gonzalez F.J.
        • Desvergne B.
        • Wahli W.
        Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting.
        J Clin Invest. 1999; 103: 1489-1498
        • Djouadi F.
        • Weinheimer C.J.
        • Saffitz J.E.
        • Pitchford C.
        • Bastin J.
        • Gonzalez F.J.
        • et al.
        A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor alpha-deficient mice.
        J Clin Invest. 1998; 102: 1083-1091
        • Badman M.K.
        • Pissios P.
        • Kennedy A.R.
        • Koukos G.
        • Flier J.S.
        • Maratos-Flier E.
        Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states.
        Cell Metab. 2007; 5: 426-437
        • Galman C.
        • Lundasen T.
        • Kharitonenkov A.
        • Bina H.A.
        • Eriksson M.
        • Hafstrom I.
        • et al.
        The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man.
        Cell Metab. 2008; 8: 169-174
        • Schoonjans K.
        • Peinado-Onsurbe J.
        • Lefebvre A.M.
        • Heyman R.A.
        • Briggs M.
        • Deeb S.
        • et al.
        PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene.
        EMBO J. 1996; 15: 5336-5348
        • Hertz R.
        • Bishara-Shieban J.
        • Bar-Tana J.
        Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III.
        J Biol Chem. 1995; 270: 13470-13475
        • Caron S.
        • Verrijken A.
        • Mertens I.
        • Samanez C.H.
        • Mautino G.
        • Haas J.T.
        • et al.
        Transcriptional activation of apolipoprotein CIII expression by glucose may contribute to diabetic dyslipidemia.
        Arterioscler Thromb Vasc Biol. 2011; 31: 513-519
        • Altomonte J.
        • Cong L.
        • Harbaran S.
        • Richter A.
        • Xu J.
        • Meseck M.
        • et al.
        Foxo1 mediates insulin action on apoC-III and triglyceride metabolism.
        J Clin Invest. 2004; 114: 1493-1503
        • Qu S.
        • Su D.
        • Altomonte J.
        • Kamagate A.
        • He J.
        • Perdomo G.
        • et al.
        PPAR{alpha} mediates the hypolipidemic action of fibrates by antagonizing FoxO1.
        Am J Physiol Endocrinol Metab. 2007; 292: E421-E434
        • Berthou L.
        • Duverger N.
        • Emmanuel F.
        • Langouet S.
        • Auwerx J.
        • Guillouzo A.
        • et al.
        Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice.
        J Clin Invest. 1996; 97: 2408-2416
        • Staels B.
        • van Tol A.
        • Andreu T.
        • Auwerx J.
        Fibrates influence the expression of genes involved in lipoprotein metabolism in a tissue-selective manner in the rat.
        Arterioscler Thromb. 1992; 12: 286-294
        • Peters J.M.
        • Hennuyer N.
        • Staels B.
        • Fruchart J.C.
        • Fievet C.
        • Gonzalez F.J.
        • et al.
        Alterations in lipoprotein metabolism in peroxisome proliferator-activated receptor alpha-deficient mice.
        J Biol Chem. 1997; 272: 27307-27312
        • Vu-Dac N.
        • Schoonjans K.
        • Kosykh V.
        • Dallongeville J.
        • Fruchart J.C.
        • Staels B.
        • et al.
        Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor.
        J Clin Invest. 1995; 96: 741-750
        • Fruchart-Najib J.
        • Bauge E.
        • Niculescu L.S.
        • Pham T.
        • Thomas B.
        • Rommens C.
        • et al.
        Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5.
        Biochem Biophys Res Commun. 2004; 319: 397-404
        • Schaap F.G.
        • Rensen P.C.
        • Voshol P.J.
        • Vrins C.
        • van der Vliet H.N.
        • Chamuleau R.A.
        • et al.
        ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis.
        J Biol Chem. 2004; 279: 27941-27947
        • Merkel M.
        • Loeffler B.
        • Kluger M.
        • Fabig N.
        • Geppert G.
        • Pennacchio L.A.
        • et al.
        Apolipoprotein AV accelerates plasma hydrolysis of triglyceride-rich lipoproteins by interaction with proteoglycan-bound lipoprotein lipase.
        J Biol Chem. 2005; 280: 21553-21560
        • Pennacchio L.A.
        • Olivier M.
        • Hubacek J.A.
        • Cohen J.C.
        • Cox D.R.
        • Fruchart J.C.
        • et al.
        An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.
        Science. 2001; 294: 169-173
        • Prieur X.
        • Lesnik P.
        • Moreau M.
        • Rodriguez J.C.
        • Doucet C.
        • Chapman M.J.
        • et al.
        Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha. Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice.
        Biochim Biophys Acta. 2009; 1791: 764-771
        • Vu-Dac N.
        • Gervois P.
        • Jakel H.
        • Nowak M.
        • Bauge E.
        • Dehondt H.
        • et al.
        Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor alpha activators.
        J Biol Chem. 2003; 278: 17982-17985
        • Brautbar A.
        • Barbalic M.
        • Chen F.
        • Belmont J.
        • Virani S.S.
        • Scherer S.
        • et al.
        Rare APOA5 promoter variants associated with paradoxical HDL cholesterol decrease in response to fenofibric acid therapy.
        J Lipid Res. 2013; 54: 1980-1987
        • Brautbar A.
        • Covarrubias D.
        • Belmont J.
        • Lara-Garduno F.
        • Virani S.S.
        • Jones P.H.
        • et al.
        Variants in the APOA5 gene region and the response to combination therapy with statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia.
        Atherosclerosis. 2011; 219: 737-742
        • Lai C.Q.
        • Arnett D.K.
        • Corella D.
        • Straka R.J.
        • Tsai M.Y.
        • Peacock J.M.
        • et al.
        Fenofibrate effect on triglyceride and postprandial response of apolipoprotein A5 variants: the GOLDN study.
        Arterioscler Thromb Vasc Biol. 2007; 27: 1417-1425
        • Cardona F.
        • Guardiola M.
        • Queipo-Ortuno M.I.
        • Murri M.
        • Ribalta J.
        • Tinahones F.J.
        The −1131T>C SNP of the APOA5 gene modulates response to fenofibrate treatment in patients with the metabolic syndrome: a postprandial study.
        Atherosclerosis. 2009; 206: 148-152
        • Ferre P.
        • Foufelle F.
        Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c.
        Diabetes Obes Metab. 2010; 12: 83-92
        • Fernandez-Alvarez A.
        • Alvarez M.S.
        • Gonzalez R.
        • Cucarella C.
        • Muntane J.
        • Casado M.
        Human SREBP1c expression in liver is directly regulated by peroxisome proliferator-activated receptor alpha (PPARalpha).
        J Biol Chem. 2011; 286: 21466-21477
        • Patel D.D.
        • Knight B.L.
        • Wiggins D.
        • Humphreys S.M.
        • Gibbons G.F.
        Disturbances in the normal regulation of SREBP-sensitive genes in PPAR alpha-deficient mice.
        J Lipid Res. 2001; 42: 328-337
        • Miller C.W.
        • Ntambi J.M.
        Peroxisome proliferators induce mouse liver stearoyl-CoA desaturase 1 gene expression.
        Proc Natl Acad Sci U S A. 1996; 93: 9443-9448
        • Knight B.L.
        • Hebbachi A.
        • Hauton D.
        • Brown A.M.
        • Wiggins D.
        • Patel D.D.
        • et al.
        A role for PPARalpha in the control of SREBP activity and lipid synthesis in the liver.
        Biochem J. 2005; 389: 413-421
        • Chen G.
        • Liang G.
        • Ou J.
        • Goldstein J.L.
        • Brown M.S.
        Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver.
        Proc Natl Acad Sci U S A. 2004; 101: 11245-11250
        • Repa J.J.
        • Liang G.
        • Ou J.
        • Bashmakov Y.
        • Lobaccaro J.M.
        • Shimomura I.
        • et al.
        Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta.
        Genes Dev. 2000; 14: 2819-2830
        • Hebbachi A.M.
        • Knight B.L.
        • Wiggins D.
        • Patel D.D.
        • Gibbons G.F.
        Peroxisome proliferator-activated receptor alpha deficiency abolishes the response of lipogenic gene expression to re-feeding: restoration of the normal response by activation of liver X receptor alpha.
        J Biol Chem. 2008; 283: 4866-4876
        • Juge-Aubry C.E.
        • Hammar E.
        • Siegrist-Kaiser C.
        • Pernin A.
        • Takeshita A.
        • Chin W.W.
        • et al.
        Regulation of the transcriptional activity of the peroxisome proliferator-activated receptor alpha by phosphorylation of a ligand-independent trans-activating domain.
        J Biol Chem. 1999; 274: 10505-10510
        • Jiang Y.
        • Cypess A.M.
        • Muse E.D.
        • Wu C.R.
        • Unson C.G.
        • Merrifield R.B.
        • et al.
        Glucagon receptor activates extracellular signal-regulated protein kinase 1/2 via cAMP-dependent protein kinase.
        Proc Natl Acad Sci U S A. 2001; 98: 10102-10107
        • Lazennec G.
        • Canaple L.
        • Saugy D.
        • Wahli W.
        Activation of peroxisome proliferator-activated receptors (PPARs) by their ligands and protein kinase A activators.
        Mol Endocrinol. 2000; 14: 1962-1975
        • Sengupta S.
        • Peterson T.R.
        • Laplante M.
        • Oh S.
        • Sabatini D.M.
        MTORC1 controls fasting-induced ketogenesis and its modulation by ageing.
        Nature. 2010; 468: 1100-1104
        • Kim K.
        • Pyo S.
        • Um S.H.
        S6 kinase 2 deficiency enhances ketone body production and increases peroxisome proliferator-activated receptor alpha activity in the liver.
        Hepatology. 2012; 55: 1727-1737
        • Jensen-Urstad A.P.
        • Song H.
        • Lodhi I.J.
        • Funai K.
        • Yin L.
        • Coleman T.
        • et al.
        Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARalpha.
        J Lipid Res. 2013; 54: 1848-1859
        • Bronner M.
        • Hertz R.
        • Bar-Tana J.
        Kinase-independent transcriptional co-activation of peroxisome proliferator-activated receptor alpha by AMP-activated protein kinase.
        Biochem J. 2004; 384: 295-305
        • Joly E.
        • Roduit R.
        • Peyot M.L.
        • Habinowski S.A.
        • Ruderman N.B.
        • Witters L.A.
        • et al.
        Glucose represses PPARalpha gene expression via AMP-activated protein kinase but not via p38 mitogen-activated protein kinase in the pancreatic beta-cell.
        J Diabetes. 2009; 1: 263-272
        • Ravnskjaer K.
        • Boergesen M.
        • Dalgaard L.T.
        • Mandrup S.
        Glucose-induced repression of PPARalpha gene expression in pancreatic beta-cells involves PP2A activation and AMPK inactivation.
        J Mol Endocrinol. 2006; 36: 289-299
        • Yoon M.J.
        • Lee G.Y.
        • Chung J.J.
        • Ahn Y.H.
        • Hong S.H.
        • Kim J.B.
        Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha.
        Diabetes. 2006; 55: 2562-2570
        • Hotta K.
        • Funahashi T.
        • Arita Y.
        • Takahashi M.
        • Matsuda M.
        • Okamoto Y.
        • et al.
        Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.
        Arterioscler Thromb Vasc Biol. 2000; 20: 1595-1599
        • Mansouri R.M.
        • Bauge E.
        • Staels B.
        • Gervois P.
        Systemic and distal repercussions of liver-specific peroxisome proliferator-activated receptor-alpha control of the acute-phase response.
        Endocrinology. 2008; 149: 3215-3223
        • Stienstra R.
        • Saudale F.
        • Duval C.
        • Keshtkar S.
        • Groener J.E.
        • van Rooijen N.
        • et al.
        Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity.
        Hepatology. 2010; 51: 511-522
        • Stienstra R.
        • Mandard S.
        • Tan N.S.
        • Wahli W.
        • Trautwein C.
        • Richardson T.A.
        • et al.
        The Interleukin-1 receptor antagonist is a direct target gene of PPARalpha in liver.
        J Hepatol. 2007; 46: 869-877
        • Kleemann R.
        • Gervois P.P.
        • Verschuren L.
        • Staels B.
        • Princen H.M.
        • Kooistra T.
        Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFkappa B-C/EBP-beta complex formation.
        Blood. 2003; 101: 545-551
        • Allard J.P.
        • Aghdassi E.
        • Mohammed S.
        • Raman M.
        • Avand G.
        • Arendt B.M.
        • et al.
        Nutritional assessment and hepatic fatty acid composition in non-alcoholic fatty liver disease (NAFLD): a cross-sectional study.
        J Hepatol. 2008; 48: 300-307
        • Tailleux A.
        • Wouters K.
        • Staels B.
        Roles of PPARs in NAFLD: potential therapeutic targets.
        Biochim Biophys Acta. 2012; 1821: 809-818
        • Ip E.
        • Farrell G.
        • Hall P.
        • Robertson G.
        • Leclercq I.
        Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice.
        Hepatology. 2004; 39: 1286-1296
        • Peters J.M.
        • Rusyn I.
        • Rose M.L.
        • Gonzalez F.J.
        • Thurman R.G.
        Peroxisome proliferator-activated receptor alpha is restricted to hepatic parenchymal cells, not Kupffer cells: implications for the mechanism of action of peroxisome proliferators in hepatocarcinogenesis.
        Carcinogenesis. 2000; 21: 823-826
        • Rommelaere S.
        • Millet V.
        • Gensollen T.
        • Bourges C.
        • Eeckhoute J.
        • Hennuyer N.
        • et al.
        PPARalpha regulates the production of serum Vanin-1 by liver.
        FEBS Lett. 2013; 587: 3742-3748
        • van Diepen J.A.
        • Jansen P.A.
        • Ballak D.B.
        • Hijmans A.
        • Hooiveld G.J.
        • Rommelaere S.
        • et al.
        PPAR-alpha dependent regulation of vanin-1 mediates hepatic lipid metabolism.
        J Hepatol. 2014; 61: 366-372
        • Jha P.
        • Claudel T.
        • Baghdasaryan A.
        • Mueller M.
        • Halilbasic E.
        • Das S.K.
        • et al.
        Role of adipose triglyceride lipase (PNPLA2) in protection from hepatic inflammation in mouse models of steatohepatitis and endotoxemia.
        Hepatology. 2014; 59: 858-869
        • Arsov T.
        • Silva D.G.
        • O’Bryan M.K.
        • Sainsbury A.
        • Lee N.J.
        • Kennedy C.
        • et al.
        Fat aussie–a new Alstrom syndrome mouse showing a critical role for ALMS1 in obesity, diabetes, and spermatogenesis.
        Mol Endocrinol. 2006; 20: 1610-1622
        • Larter C.Z.
        • Yeh M.M.
        • Van Rooyen D.M.
        • Teoh N.C.
        • Brooling J.
        • Hou J.Y.
        • et al.
        Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice.
        J Gastroenterol Hepatol. 2009; 24: 1658-1668
        • Collin G.B.
        • Cyr E.
        • Bronson R.
        • Marshall J.D.
        • Gifford E.J.
        • Hicks W.
        • et al.
        Alms1-disrupted mice recapitulate human Alstrom syndrome.
        Hum Mol Genet. 2005; 14: 2323-2333
        • Larter C.Z.
        • Yeh M.M.
        • Van Rooyen D.M.
        • Brooling J.
        • Ghatora K.
        • Farrell G.C.
        Peroxisome proliferator-activated receptor-alpha agonist, Wy 14,643, improves metabolic indices, steatosis and ballooning in diabetic mice with non-alcoholic steatohepatitis.
        J Gastroenterol Hepatol. 2011; 27: 341-350
        • Abdelmegeed M.A.
        • Yoo S.H.
        • Henderson L.E.
        • Gonzalez F.J.
        • Woodcroft K.J.
        • Song B.J.
        PPARalpha expression protects male mice from high fat-induced nonalcoholic fatty liver.
        J Nutr. 2011; 141: 603-610
        • Guerre-Millo M.
        • Gervois P.
        • Raspe E.
        • Madsen L.
        • Poulain P.
        • Derudas B.
        • et al.
        Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity.
        J Biol Chem. 2000; 275: 16638-16642
        • Tordjman K.
        • Bernal-Mizrachi C.
        • Zemany L.
        • Weng S.
        • Feng C.
        • Zhang F.
        • et al.
        PPARalpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice.
        J Clin Invest. 2001; 107: 1025-1034
        • Haluzik M.
        • Gavrilova O.
        • LeRoith D.
        Peroxisome proliferator-activated receptor-alpha deficiency does not alter insulin sensitivity in mice maintained on regular or high-fat diet: hyperinsulinemic-euglycemic clamp studies.
        Endocrinology. 2004; 145: 1662-1667
        • Haluzik M.M.
        • Haluzik M.
        PPAR-alpha and insulin sensitivity.
        Physiol Res. 2006; 55: 115-122
        • Shiri-Sverdlov R.
        • Wouters K.
        • van Gorp P.J.
        • Gijbels M.J.
        • Noel B.
        • Buffat L.
        • et al.
        Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates.
        J Hepatol. 2006; 44: 732-741
        • Lalloyer F.
        • Wouters K.
        • Baron M.
        • Caron S.
        • Vallez E.
        • Vanhoutte J.
        • et al.
        Peroxisome proliferator-activated receptor-alpha gene level differently affects lipid metabolism and inflammation in apolipoprotein E2 knock-in mice.
        Arterioscler Thromb Vasc Biol. 2011; 31: 1573-1579
        • Jun H.J.
        • Kim J.
        • Hoang M.H.
        • Lee S.J.
        Hepatic lipid accumulation alters global histone h3 lysine 9 and 4 trimethylation in the peroxisome proliferator-activated receptor alpha network.
        PLoS One. 2012; 7: e44345
        • Svegliati Baroni G.
        • D’Ambrosio L.
        • Ferretti G.
        • Casini A.
        • Di Sario A.
        • Salzano R.
        • et al.
        Fibrogenic effect of oxidative stress on rat hepatic stellate cells.
        Hepatology. 1998; 27: 720-726
        • De Bleser P.J.
        • Xu G.
        • Rombouts K.
        • Rogiers V.
        • Geerts A.
        Glutathione levels discriminate between oxidative stress and transforming growth factor-beta signaling in activated rat hepatic stellate cells.
        J Biol Chem. 1999; 274: 33881-33887
        • Toyama T.
        • Nakamura H.
        • Harano Y.
        • Yamauchi N.
        • Morita A.
        • Kirishima T.
        • et al.
        PPARalpha ligands activate antioxidant enzymes and suppress hepatic fibrosis in rats.
        Biochem Biophys Res Commun. 2004; 324: 697-704
        • Rodriguez-Vilarrupla A.
        • Lavina B.
        • Garcia-Caldero H.
        • Russo L.
        • Rosado E.
        • Roglans N.
        • et al.
        PPARalpha activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats.
        J Hepatol. 2012; 56: 1033-1039
        • Fernandez-Miranda C.
        • Perez-Carreras M.
        • Colina F.
        • Lopez-Alonso G.
        • Vargas C.
        • Solis-Herruzo J.A.
        A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease.
        Dig Liver Dis. 2008; 40: 200-205
        • Nakamuta M.
        • Morizono S.
        • Soejima Y.
        • Yoshizumi T.
        • Aishima S.
        • Takasugi S.
        • et al.
        Short-term intensive treatment for donors with hepatic steatosis in living-donor liver transplantation.
        Transplantation. 2005; 80: 608-612
        • Basaranoglu M.
        • Acbay O.
        • Sonsuz A.
        A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis.
        J Hepatol. 1999; 31: 384
        • Laurin J.
        • Lindor K.D.
        • Crippin J.S.
        • Gossard A.
        • Gores G.J.
        • Ludwig J.
        • et al.
        Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study.
        Hepatology. 1996; 23: 1464-1467
        • Holden P.R.
        • Tugwood J.D.
        Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences.
        J Mol Endocrinol. 1999; 22: 1-8
        • Palmer C.N.
        • Hsu M.H.
        • Griffin K.J.
        • Raucy J.L.
        • Johnson E.F.
        Peroxisome proliferator activated receptor-alpha expression in human liver.
        Mol Pharmacol. 1998; 53: 14-22
        • Cariou B.
        • Zair Y.
        • Staels B.
        • Bruckert E.
        Effects of the new dual PPAR alpha/delta agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism.
        Diabetes Care. 2011; 34: 2008-2014
        • Cariou B.
        • Hanf R.
        • Lambert-Porcheron S.
        • Zair Y.
        • Sauvinet V.
        • Noel B.
        • et al.
        Dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects.
        Diabetes Care. 2013; 36: 2923-2930
        • Parker H.M.
        • Johnson N.A.
        • Burdon C.A.
        • Cohn J.S.
        • O’Connor H.T.
        • George J.
        Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis.
        J Hepatol. 2012; 56: 944-951
        • Lu Y.
        • Boekschoten M.V.
        • Wopereis S.
        • Muller M.
        • Kersten S.
        Comparative transcriptomic and metabolomic analysis of fenofibrate and fish oil treatments in mice.
        Physiol Genomics. 2011; 43: 1307-1318