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The interaction of hepatic lipid and glucose metabolism in liver diseases

Open AccessPublished:December 14, 2011DOI:https://doi.org/10.1016/j.jhep.2011.08.025

      Summary

      It is widely known that the liver is a central organ in lipogenesis, gluconeogenesis and cholesterol metabolism. However, over the last decades, a variety of pathological conditions highlighted the importance of metabolic functions within the diseased liver. As observed in Western societies, an increase in the prevalence of obesity and the metabolic syndrome promotes pathophysiological changes that cause non-alcoholic fatty liver disease (NAFLD). NAFLD increases the susceptibility of the liver to acute liver injury and may lead to cirrhosis and hepatocellular cancer. Alterations in insulin response, β-oxidation, lipid storage and transport, autophagy and an imbalance in chemokines and nuclear receptor signaling are held accountable for these changes. Furthermore, recent studies revealed a role for lipid accumulation in inflammation and ER stress in the clinical context of liver regeneration and hepatic carcinogenesis. This review focuses on novel findings related to nuclear receptor signaling – including the vitamin D receptor and the liver receptor homolog 1 – in hepatic lipid and glucose uptake, storage and metabolism in the clinical context of NAFLD, liver regeneration, and cancer.
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      Abbreviations:

      ACC (acetyl-CoA carboxylase), ATF6 (activating transcription factor-6), AMPK (AMP-activated protein kinase), apoB-48/100 (apoprotein B-48/100), BA (bile acids), CD36/FAT (fatty acid translocase), ChREBP (carbohydrate responsive element binding protein), CPT-1 (carnitine palmitoyltransferase-1), DAG (diacylglycerol), DGAT (diacylglycerol-acyltransferase), DNL (de novo lipogenesis), ER (endoplasmatic reticulum), FA (fatty acids), FABP (fatty acid binding protein), FAS (fatty acid synthase), FATPs (fatty acid transport proteins), FFA (free FA), FGF15/19 (fibroblast growth factors 15 (mouse) and 19 (human)), FoxO (forkhead box protein O), FXR (farnesoid X receptor), GCKR (glucokinase regulatory protein), GLP-1 (glucagon like peptide-1), GLUT2 (glucose transporter type 2), Got2 or mitochondrial aspartate aminotransferase [mAspAT] (glutamate-oxaloacetate-transaminase 2), GPAT (glycerol-3-phosphate-acyltransferase), GS (glycogen synthase), G6Pase (glucose-6-phosphase), HCC (Hepatocellular carcinoma), HNF4α (hepatic nuclear factor-4-alpha), HNF6 (hepatic nuclear factor 6), IGF-1 (insulin-like-growth factor 1), IR (insulin resistance), LCFAs (long chain fatty acids), L-GCK (liver glucokinase), LRH1 (liver receptor homolog 1), LXR (liver X receptor), MODY (maturity onset diabetes of the young), mTOR (mmmalian target of rapamycin), NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis), NRs (nuclear receptors), PEPCK (phosphoenolpyruvate carboxykinase), PGC1α (peroxisome proliferator-activated receptor γ co-activator-1α), PHx (partial hepatectomy), PI3K (phosphoinositide-3-kinase), PKA (protein kinase A), PPARs (peroxisome proliferator-activated receptors), PYGL (glycogen phosphorylase), ROS (reactive oxygen species), SIRT1 (sirtuin 1), SREBP-1c (sterol-response-binding-protein-1c), TAGs (triacylglycerols), TCA (tricarboxylic acid cycle), TRB3 (tribbles-homologue 3), UPR (unfolded protein response), USF1 (upstream stimulatory factor 1), VDR (vitamin D receptor), VLDL (very low-density lipoproteins)

      Keywords

      Introduction

      As the main detoxifying organ of the body, the liver also plays a central role in metabolic homeostasis and is a major site for synthesis, metabolism, storage and redistribution of carbohydrates, proteins and lipids. The rapid increase in obesity worldwide is associated with an increase in the prevalence of non-alcoholic fatty liver disease (NAFLD), making NAFLD the most common liver disease in Western societies [
      • Feldstein A.E.
      Novel insights into the pathophysiology of nonalcoholic fatty liver disease.
      ,
      • Browning J.D.
      • Szczepaniak L.S.
      • Dobbins R.
      • Nuremberg P.
      • Horton J.D.
      • Cohen J.C.
      • et al.
      Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.
      ]. In order to understand the pathogenesis of NAFLD, we discuss the basic physiologic mechanisms of hepatic lipid and glucose metabolism. We also aimed at integrating recent clinical and mechanistic data and point out novel links between basic metabolic pathways and the pathophysiologies of NAFLD, liver regeneration, and carcinogenesis.
      NAFLD is characterized by lipid accumulation within hepatocytes and may progress to non-alcoholic steatohepatitis (NASH). Lipids derive from circulating fatty acids (FA) upon insulin resistance (IR)-induced dysregulation of peripheral lipolysis. FAs are translocated into the hepatocyte mainly by membrane bound transport proteins [
      • Donnelly K.L.
      • Smith C.I.
      • Schwarzenberg S.J.
      • Jessurun J.
      • Boldt M.D.
      • Parks E.J.
      Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
      ]. De novo lipogenesis (DNL) further contributes to hepatic steatosis [
      • Postic C.
      • Girard J.
      Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance. lessons from genetically engineered mice.
      ]. Hepatocellular accumulation of lipotoxic intermediates such as diacylglycerol (DAG) and ceramids causes hepatic IR [
      • Samuel V.T.
      • Petersen K.F.
      • Shulman G.I.
      Lipid-induced insulin resistance. unravelling the mechanism.
      ]. Hepatocytic lipid accumulation predisposes to overproduction of reactive oxygen species (ROS), endoplasmatic reticulum (ER) stress and lipotoxicity [
      • Sanyal A.J.
      • Campbell-Sargent C.
      • Mirshahi F.
      • Rizzo W.B.
      • Contos M.J.
      • Sterling R.K.
      • et al.
      Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities.
      ,
      • Neuschwander-Tetri B.A.
      Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites.
      ,
      • Fu S.
      • Yang L.
      • Li P.
      • Hofmann O.
      • Dicker L.
      • Hide W.
      • et al.
      Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity.
      ]. Recently, autophagy (especially in the form of macrolipophagy) has been identified to regulate intracellular lipid stores through degradation of lipid droplets and release of FAs into the cytosol as a rapid response to starvation [
      • Rautou P.E.
      • Mansouri A.
      • Lebrec D.
      • Durand F.
      • Valla D.
      • Moreau R.
      Autophagy in liver diseases.
      ,
      • Singh R.
      • Kaushik S.
      • Wang Y.
      • Xiang Y.
      • Novak I.
      • Komatsu M.
      • et al.
      Autophagy regulates lipid metabolism.
      ,
      • Wang Y.
      • Singh R.
      • Xiang Y.
      • Czaja M.J.
      Macroautophagy and chaperone-mediated autophagy are required for hepatocyte resistance to oxidant stress.
      ]. Thus, disrupted autophagy might be essential to the pathogenesis of NASH via lipotoxicity-induced ER stress [
      • Yang L.
      • Li P.
      • Fu S.
      • Calay E.S.
      • Hotamisligil G.S.
      Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance.
      ].
      The individual steps in hepatic lipid metabolism are orchestrated by a delicate interplay of hormones, nuclear receptors, intracellular signaling pathways and transcription factors. Insulin signaling plays an important role in the regulation of FA metabolism, underscoring the close relation between lipid and glucose metabolism. Insulin affects DNL on multiple levels, via induction of lipogenic genes, activation of sterol-response-binding-protein-1c (SREBP-1c) and Akt-regulated production of very low-density lipoproteins (VLDLs) [
      • Savage D.B.
      • Semple R.K.
      Recent insights into fatty liver, metabolic dyslipidaemia and their links to insulin resistance.
      ]. Insulin, along with other mediators (e.g., calpain-1), further represses autophagy within the hepatocyte, and thus induces lipogenesis and represses lipid-degradation in the fed state as well [
      • Rautou P.E.
      • Mansouri A.
      • Lebrec D.
      • Durand F.
      • Valla D.
      • Moreau R.
      Autophagy in liver diseases.
      ,
      • Yang L.
      • Li P.
      • Fu S.
      • Calay E.S.
      • Hotamisligil G.S.
      Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance.
      ]. On the other hand, glucagon-like peptide-1 (GLP-1) also alters hepatic lipid metabolism [
      • Gupta N.A.
      • Mells J.
      • Dunham R.M.
      • Grakoui A.
      • Handy J.
      • Saxena N.K.
      • et al.
      Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway.
      ]. FA oxidation and the expression of fatty acid transport proteins (FATPs) are closely regulated by the nuclear receptor peroxisome proliferator-activated receptor (PPAR)α, and in the steatotic liver also by PPARγ [
      • Pyper S.R.
      • Viswakarma N.
      • Yu S.
      • Reddy J.K.
      PPARalpha: energy combustion, hypolipidemia, inflammation and cancer.
      ].
      In the following paragraphs, we will discuss the function of hepatic lipid and glucose metabolism under normal conditions and their roles in NAFLD, acute liver injury and regeneration as well as hepatic carcinogenesis. This review focuses on the central role of nuclear receptor signaling in hepatic glucose and lipid metabolism including novel mechanisms like vitamin D receptor (VDR) and liver receptor homolog 1 (LRH1) signaling, autophagy and the interrelation of ER stress and metabolism Table 1.
      Table 1Overview of ligands and function of the most abundant nuclear receptors in hepatocytes.

      Hepatic lipid metabolism

      Extrahepatic lipid metabolism

      Lipid metabolism starts with the intestinal absorption of dietary fats. In order to cross the intestinal lumen into the plasma, lipids are emulsified and hydrolyzed within the lumen. The healthy liver is crucial for intestinal lipid absorption via bile acids (BA) that are synthesized within the hepatocyte and secreted into the bile duct to emulsify lipid droplets by their amphiphilic properties rendering them accessible to lipase hydrolyzation. Hydrolyzed lipids are then absorbed by enterocytes, where lipids are re-synthesized and packed into lipoprotein particles (i.e., nascent chylomicrons).
      Nascent chylomicrons are secreted into the lymphatic system, where they bypass the liver and enter the circulation within two hours after food intake [
      • Timlin M.T.
      • Parks E.J.
      Temporal pattern of de novo lipogenesis in the postprandial state in healthy men.
      ]. During their journey through the vascular system, nascent chylomicrones lose two minor apoproteins (apoA-I and apoA-IV), which are replaced by apoE and apoC-II that are crucial for their further processing. ApoC-II activates adipocyte lipoprotein lipase (LPL), which facilitates the digestion of the chylomicron triacylglycerols (TAGs) into FAs and glycerol [
      • Merkel M.
      • Eckel R.H.
      • Goldberg I.J.
      Lipoprotein lipase: genetics, lipid uptake, and regulation.
      ]. FAs are then partially taken up and stored in adipocytes, while chylomicron remnants re-enter the blood stream. ApoE is then recognized by the hepatocyte LDL receptor, the LDL receptor-related protein (LRP) and scavenger receptor B-1, which facilitate endocytotic uptake of the chylomicron remnants. As cholesteryl-ester enriched and triglyceride-depleted products of chylomicron metabolism, chylomicron remnants are finally processed by intracellular lysosomes – and their glycerol, FA, cholesterol, amino acid and phosphate residues are metabolized and recycled into new VLDLs (see Fig. 1A for overview).
      Figure thumbnail gr1
      Fig. 1Hepatic lipid metabolism in health and disease. (A) Dietary lipids are emulsified in the intestinal tract by bile acids (BAs). Hydrolyzed lipids are absorbed by enterocytes and packed into nascent chylomicrons (NCs). NCs enter the bloodstream via the thoracic duct where they receive important apoproteins (apoE; apoC-II) from HDL. These apoproteins are important for chylomicrons (C) to deliver TAGs and FAs to adipocytes and myocytes via lipoprotein lipase (LPL) degradation. Chylomicron remnants are taken up by hepatocytes via LDL-receptor (LDLR) and LDL receptor-related protein (LRP)-mediated endocytosis. BA synthesis is regulated by LRH1 and FXR, which activate BA export pumps. BA re-uptake by enterocytes stimulates FGF-19 release into the portal blood, which inhibits BA synthesis. (B) Free fatty acids (FFA) derive from lipolysis in adipose tissue and are actively taken up by various FA transporters under the control of insulin (Ins) and nuclear receptor signaling. Under physiologic conditions, the bulk of FAs is oxidized intramitochondrially and provides ATP and acetyl-CoA for the tricarboxylic acid cycle (TCA). Triglycerides (TAGs) derived from de novo lipogenesis are either stored in lipid droplets (LD) or packed into VLDL and exported into the blood stream. Acetyl-CoA for de novo lipogenesis is provided by the pyruvate dehydrogenase complex (PDC), which catalyzes oxidation of pyruvate, the end product of glycolysis. (C) Under physiologic conditions, β-oxidation of short-, medium- and long-chain FAs (SCFA, MCFA, LCFA) are degraded in mitochondria. Therefore, FAs are activated to acyl-CoA and shuttled across the mitochondrial membrane by carnitine palmitoyltransferase-1 (CPT1). Malonyl-CoA, an intermediate of lipogenesis, inhibits CPT1 and thus FA oxidation in the mitochondria. With FA abundance and in the insulin resistant state, LCFA and very-long-chain FAs (VLCFA) are oxidized in peroxisomes and the ER. This leads to an abundance of metabolites that induce formation of ROS and contribute to lipotoxicity. (D) In NASH, increased peripheral lipolysis, upregulation of FA transporters, an increase in DNL, and a switch from mitochondrial β-oxidation to peroxisomal and ω-oxidation promote FA toxicity and the release of ROS. This leads to the induction of hepatocyte apoptosis, the invasion and activation of inflammatory cells, as well as fibrogenesis.

      Hepatic lipogenesis

      As mentioned above, hepatic FAs either derive from endogenous lipogenesis, are released from lysosomes by autophagy, or derive from the free FA (FFA) plasma pool via active uptake into the hepatocyte. Depending on the metabolic state, FAs are then either processed to TAGs and stored or rapidly metabolized. Indeed, β-oxidation is the predominant source of energy during the fasting state.
      Hepatic lipogenesis includes de novo synthesis of FAs from acetyl-CoA or malonyl-CoA and further processing to TAGs. In mammals, FA synthesis is catalyzed by acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) – an enzyme that is complexly regulated by various nuclear receptors (PPARα, PPARγ and the bile acid receptor/farnesoid X receptor [FXR]) [
      • 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.
      ,
      • Schadinger S.E.
      • Bucher N.L.
      • Schreiber B.M.
      • Farmer S.R.
      PPARgamma2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes.
      ,
      • Shen L.L.
      • Liu H.
      • Peng J.
      • Gan L.
      • Lu L.
      • Zhang Q.
      • et al.
      Effects of farnesoid X receptor on the expression of the fatty acid synthetase and hepatic lipase.
      ]. FA elongation requires NADPH as a reducing reagent, which is provided by the pentose phosphate pathway (Fig. 2B). Remarkably, PPARα itself is activated by a phospholipid synthesized by FAS, indicating a feedback loop [
      • 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.
      ].
      Figure thumbnail gr2
      Fig. 2Regulation of hepatic glucose metabolism. (A) After intestinal absorption, glucose (Glu) reaches the hepatocyte via the portal vein. The insulin-independent glucose transporter 2 (GLUT2) shuttles Glu across the membrane. Abundance of glucose induces conformational changes of the glucokinase regulatory protein (GCKR), which binds to glucokinase (GCK) and keeps it in the nucleus in the fasting state. GCK is then released into the cytosol and phosphorylates Glu to glucose-6-phosphate (Glu-6-P); depending on the nutritional state, it serves as a substrate for glycolysis or glycogen synthesis, respectively. GCK is transcriptionally regulated by insulin and nuclear receptor signaling. (B) Glu-6-P is a central intermediate in the hepatic glucose metabolism. It is degraded during glycolysis, which provides energy in the form of two ATP and two NADH molecules per glucose molecule. The product pyruvate is further decarboxylized to acetyl-CoA, which enters the intramitochondrial tricarboxylic acid cycle (TCA). Alternatively, Glu-6-P is degraded in the pentose-phosphate shunt, which provides NADPH, a co-substrate for DNL. Acetyl-CoA is an important product of the TCA, linking glucose and lipid metabolism, as it is the substrate for DNL (). Gluconeogenesis and glycogenolysis provide Glu-6-P as a substrate for glucose synthesis in the fasting state. Glucogenolysis is catalyzed by glycogen phosphorylase, activated by AMP, and repressed by insulin. The key enzyme in gluconeogenesis is PEPCK, which is repressed by insulin signaling via Akt-mediated FoxO phosphorylation and activated by PPARα.
      A close link between glucose and lipid metabolism is indicated by the fact that nuclear receptors (NRs) are also important mediators of insulin signaling and since DNL occurs under anabolic condition. The existence of such a link is further supported by the fact that insulin stimulates FAS expression via the phosphoinositide-3-kinase (PI3K) pathway [
      • Sul H.S.
      • Latasa M.J.
      • Moon Y.
      • Kim K.H.
      Regulation of the fatty acid synthase promoter by insulin.
      ]. On a transcriptional level, SREBP-1c and carbohydrate-responsive element binding protein (ChREBP), a glucose dependant transcription factor, synergistically induce expression of FAS and ACC [
      • Dentin R.
      • Girard J.
      • Postic C.
      Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver.
      ].
      As FAs and their metabolites are the major cause for lipotoxicity and promote the formation of ROS, FAs are stored for future use as TAGs, which are relatively inert and consist of three FAs esterified to a glycerol backbone. TAGs are then either stored in lipid droplets within the hepatocyte or processed to VLDL [
      • Neuschwander-Tetri B.A.
      Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites.
      ]. TAG synthesis is catalyzed by the enzymes mitochondrial glycerol-3-phosphate-acyltransferase (mtGPAT) and diacylglycerol-acyltransferase (DGAT) [
      • Coleman R.A.
      • Lee D.P.
      Enzymes of triacylglycerol synthesis and their regulation.
      ]. TAGs are then packaged into VLDL particles, by conjugation to apoB-100 in a 5:1 TAG/cholesterol ratio. These processes are controlled by SREBP-1c, the liver X receptor (LXR), FXR and ChREBP, which again links glucose and lipid metabolism [
      • Postic C.
      • Girard J.
      The role of the lipogenic pathway in the development of hepatic steatosis.
      ].

      Hepatic fatty acid uptake

      Another source for hepatic FAs is FFA recruitment from the plasma pool. FFAs are derived from lipolysis in adipocytes. This occurs usually in the fasting state, where it is promoted by catecholamines, natriuretic peptides and glucagon, while it is usually repressed by insulin [
      • Arner P.
      Human fat cell lipolysis: biochemistry, regulation and clinical role.
      ]. However, the insulin-resistant state (obesity; metabolic syndrome) goes along with increased adipocyte lipolysis, leading to abundant FFAs in the plasma pool independently from the nutritional status [
      • Delarue J.
      • Magnan C.
      Free fatty acids and insulin resistance.
      ]. FFAs are then taken up by the hepatocytes in a facilitated fashion rather than by passive processes [
      • Berk P.D.
      Regulatable fatty acid transport mechanisms are central to the pathophysiology of obesity, fatty liver, and metabolic syndrome.
      ]. FATPs are thus in the focus of NAFLD research in which a variety of FATPs have been identified. While FATP1 is abundant in muscle and adipose tissue and is barely detectable in the liver [
      • Martin G.
      • Nemoto M.
      • Gelman L.
      • Geffroy S.
      • Najib J.
      • Fruchart J.C.
      • et al.
      The human fatty acid transport protein-1 (SLC27A1; FATP-1) cDNA and gene: organization, chromosomal localization, and expression.
      ], FATP2 and FATP5 are expressed in hepatocytes and most likely facilitate the major amount of FA uptake in the liver [
      • Ge F.
      • Zhou S.
      • Hu C.
      • Lobdell Ht
      • Berk P.D.
      Insulin- and leptin-regulated fatty acid uptake plays a key causal role in hepatic steatosis in mice with intact leptin signaling but not in ob/ob or db/db mice.
      ]. Other transport proteins include fatty acid binding protein (FABP), glutamate–oxaloacetate-transaminase 2 (Got2; or mitochondrial aspartate aminotransferase [mAspAT], a membrane bound protein that mediates the endocytotic uptake of long-chain FAs), and caveolin-1 [
      • Zhou S.L.
      • Stump D.
      • Sorrentino D.
      • Potter B.J.
      • Berk P.D.
      Adipocyte differentiation of 3T3–L1 cells involves augmented expression of a 43-kDa plasma membrane fatty acid-binding protein.
      ,
      • Zhou S.L.
      • Stump D.
      • Kiang C.L.
      • Isola L.M.
      • Berk P.D.
      Mitochondrial aspartate aminotransferase expressed on the surface of 3T3–L1 adipocytes mediates saturable fatty acid uptake.
      ,
      • Trigatti B.L.
      • Anderson R.G.
      • Gerber G.E.
      Identification of caveolin-1 as a fatty acid binding protein.
      ]. Fatty acid translocase (CD36/FAT) is a membrane glycoprotein present on platelets, mononuclear phagocytes, adipocytes and hepatocytes with multiple functions, including thrombospondin-1 receptor activity, which has also been identified to facilitate FA uptake [
      • Abumrad N.A.
      • el-Maghrabi M.R.
      • Amri E.Z.
      • Lopez E.
      • Grimaldi P.A.
      Cloning of a rat adipocyte membrane protein implicated in binding or transport of long-chain fatty acids that is induced during preadipocyte differentiation. Homology with human CD36.
      ,
      • Silverstein R.L.
      • Febbraio M.
      CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior.
      ]. Besides the fact that the regulation of FATP activity is generally complex, the individual contribution of these FATPs to FA uptake has not been entirely clarified yet. Nevertheless, signaling via PPARα again predominantly regulates the transcription of these transport proteins as combined with hormonal regulation via insulin and leptin [
      • Ge F.
      • Zhou S.
      • Hu C.
      • Lobdell Ht
      • Berk P.D.
      Insulin- and leptin-regulated fatty acid uptake plays a key causal role in hepatic steatosis in mice with intact leptin signaling but not in ob/ob or db/db mice.
      ,
      • Wierzbicki M.
      • Chabowski A.
      • Zendzian-Piotrowska M.
      • Gorski J.
      Differential effects of in vivo PPAR alpha and gamma activation on fatty acid transport proteins expression and lipid content in rat liver.
      ].

      Macroautophagy

      Autophagy has recently been implied to play a role in hepatic lipid homeostasis [
      • Czaja M.J.
      Autophagy in health and disease. 2. Regulation of lipid metabolism and storage by autophagy: pathophysiological implications.
      ]. As a lysosomal pathway, it recycles dispensable cellular constituents into important energy sources during the fasting state [
      • Finn P.F.
      • Dice J.F.
      Proteolytic and lipolytic responses to starvation.
      ]. Recent animal studies revealed that autophagy is a key process in hepatic lipolysis and lipid droplet degradation [
      • Singh R.
      • Kaushik S.
      • Wang Y.
      • Xiang Y.
      • Novak I.
      • Komatsu M.
      • et al.
      Autophagy regulates lipid metabolism.
      ,
      • Shibata M.
      • Yoshimura K.
      • Furuya N.
      • Koike M.
      • Ueno T.
      • Komatsu M.
      • et al.
      The MAP1-LC3 conjugation system is involved in lipid droplet formation.
      ]. As mentioned above, lysosomes process chylomicron remnants as well as TAGs that accumulate during hepatic lipogenesis. During starvation, macroautophagy leads to the fusion of lysosomes and lipid droplets into autophagosomes, which are then degraded; FAs are thus released and can be catabolized via β-oxidation. Starvation leads to repression of the so-called mammalian target of rapamycin (mTOR), an insulin downstream target that inhibits autophagy. Interestingly, rapamycin treatment also downregulates SREBP-1c in primary hepatocytes, which suggests an effect of rapamycin, independent of mTOR, on the activity of forkhead box protein O (FoxO) [
      • Li S.
      • Brown M.S.
      • Goldstein J.L.
      Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis.
      ]. Long-term repression of autophagy is accounted for by insulin action, and Akt mediated de-phosphorylation of FoxO, a transcriptional activator of autophagy related genes (ATGs). Indeed, FoxO simultaneously represses SREBP-1c activation and thus DNL. Thus, insulin receptor activation induces DNL and represses autophagy-mediated lipid droplet degradation, both short- and long-term, via two distinct mechanisms. However, in the insulin-resistant state and in obesity per se, hepatic mTOR is over-activated and calpain, a repressor of ATGs, is induced [
      • Rautou P.E.
      • Mansouri A.
      • Lebrec D.
      • Durand F.
      • Valla D.
      • Moreau R.
      Autophagy in liver diseases.
      ]. Despite FoxO activation in IR, mTOR and calpain activation account for the repression of hepatic autophagy in obese individuals.

      Hepatic glucose metabolism

      Hepatocyte glucose uptake

      In the postprandial state, blood glucose is taken up by the hepatocyte via the glucose transporter type 2 (GLUT2) – a membrane-bound transporter with high capacity and low affinity for glucose. In contrast to GLUT4, which is expressed by muscle and adipose tissue, the expression and activity of GLUT2 is independent of insulin signaling. In pancreatic islet cells, GLUT2 is thus also referred to as a “glucose sensor” [
      • Leturque A.
      • Brot-Laroche E.
      • Le Gall M.
      GLUT2 mutations, translocation, and receptor function in diet sugar managing.
      ]. Once taken up by the hepatocyte, glucose is phosphorylated to glucose-6-phosphate by liver glucokinase (L-GCK; Fig. 2), the rate limiting enzyme for hepatic glucose utilization [
      • Agius L.
      Glucokinase and molecular aspects of liver glycogen metabolism.
      ]. In contrast to other hexokinases, GCK (syn.: hexokinase IV) is not inhibited by its product, which allows for postprandial glycogen storage within the hepatocyte. In the fasting state, L-GCK is inactive and bound to glucokinase regulatory protein (GCKR) within the nucleus. Post-prandial glucose abundance and insulin-action synergistically cause rapid dissociation of L-GCK from GCKR and translocation to the cytoplasm [
      • Chu C.A.
      • Fujimoto Y.
      • Igawa K.
      • Grimsby J.
      • Grippo J.F.
      • Magnuson M.A.
      • et al.
      Rapid translocation of hepatic glucokinase in response to intraduodenal glucose infusion and changes in plasma glucose and insulin in conscious rats.
      ]. L-GCK is transcriptionally regulated by SREBP-1c, hepatic nuclear factor-4-alpha (HNF4α), hepatic nuclear factor 6 (HNF6), FoxO1, and upstream stimulatory factor 1 (USF1) (see Fig. 2A). Indeed, mutations in the GCK gene have been associated with IR and the pathogenesis of maturity-onset diabetes of the young (MODY) in several studies [
      • Miller S.P.
      • Anand G.R.
      • Karschnia E.J.
      • Bell G.I.
      • LaPorte D.C.
      • Lange A.J.
      Characterization of glucokinase mutations associated with maturity-onset diabetes of the young type 2 (MODY-2): different glucokinase defects lead to a common phenotype.
      ,
      • Cuesta-Munoz A.L.
      • Tuomi T.
      • Cobo-Vuilleumier N.
      • Koskela H.
      • Odili S.
      • Stride A.
      • et al.
      Clinical heterogeneity in monogenic diabetes caused by mutations in the glucokinase gene (GCK-MODY).
      ].

      Glycolysis and glycogen synthesis

      Glucose-6-phosphate is either further processed in glycolysis or utilized for glycogen synthesis, depending on the systemic metabolic state. Glycolysis, a ten-step process, metabolizes glucose to pyruvate with a net gain of two ATP and two NADH molecules per glucose molecule. Glycolysis is regulated by L-GCK, which provides glucose-6-phosphate, phosphofructokinase, which is inhibited by its product fructose-1,6-bisphosphate, AMP and pyruvate-kinase (PK), the final step in glycolysis. PK is activated by its substrate and inhibited by abundance of ATP. Insulin, epinephrine, and glucagon also regulate PK via the PI3K pathway and ChREBP induces transcription of PK in the presence of glucose [
      • Dentin R.
      • Girard J.
      • Postic C.
      Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver.
      ]. Pyruvate is further decarboxylized to acetyl-CoA and then processed in the TCA or utilized for DNL. The pentose phosphate pathway is an alternative way for degradation of glucose-6-phosphate in hepatocytes, which provides the cell with NADPH, an important antioxidant and co-substrate for DNL and cholesterol synthesis. In hepatocellular carcinoma (HCC), glycolytic activity is dramatically upregulated and associated with increased hexokinase 2 activity and expression of GLUT1, leading to altered glucose utilization, which has therapeutic and diagnostic implications (for the so-called Warburg effect, Fig. 3B and C) [
      • Amann T.
      • Hellerbrand C.
      GLUT1 as a therapeutic target in hepatocellular carcinoma.
      ].
      Figure thumbnail gr3
      Fig. 3Hepatic lipid and glucose metabolism in HCC. (A) Mediators of NAFLD progression also contribute to carcinogenesis in the liver. In general, obesity and diabetes have been identified as risk factors for cancer development as well as inflammation. Cirrhosis is a precancerous condition and, in fact, most HCCs derive from cirrhotic livers. Important mediators of insulin resistance and lipotoxicity also induce dysplasia and carcinogenesis. This figure gives a brief overview of different cytokines and cell signaling pathways involved in HCC development. (B) Expression of GLUT1 in hepatoma cells leads to increased hepatic glucose utilization. Glucokinase is downregulated, but hexokinase 2 (HK2) is now expressed and phosphorylates glucose with a higher affinity. Aerobic glycolysis leads to a rapid, but rather ineffective energy supply to the proliferating cancer cell. However, this process, referred to as the Warburg effect, facilitates uptake and de novo synthesis of nutrients (nucleotides, amino acids, lipids), available for cell proliferation and tumor growth. (C) Clinically, this effect is utilized in PET diagnostics. An increase in cancer cell glucose uptake, as visualized by FDG PET/CT, acts as an important tool in HCC diagnostics.
      Glycogen synthesis is catalyzed by glycogen synthase (GS) after conversion of glucose-6-phosphate to UDP-glucose [
      • Roach P.J.
      Glycogen and its metabolism.
      ]. GS is regulated by the allosteric activator glucose-6-phosphate and is inactive in the phosphorylated state. Glycogen synthase kinase 3 (GSK3) phosphorylates GS and is a downstream target of Akt/PI3K and thus insulin signaling. GSK3 is a multifunctional kinase, involved in cell senescence, apoptosis and lipid metabolism via phosphorylation of SREBP-1c [
      • Kim Y.M.
      • Seo Y.H.
      • Park C.B.
      • Yoon S.H.
      • Yoon G.
      Roles of GSK3 in metabolic shift toward abnormal anabolism in cell senescence.
      ]. Other protein kinases that phosphorylate GS are AMP-activated protein kinase (AMPK) and protein kinase A (PKA). Insulin activates glycogen synthesis via repression of PKA. GS synthesizes the glycogen polymer, which is further branched by a branching enzyme.

      Glycogenolysis and gluconeogenesis

      In the fasting state, the liver supplies the body with energy by breaking down glycogen, and following prolonged fasting by gluconeogenesis [
      • Raddatz D.
      • Ramadori G.
      Carbohydrate metabolism and the liver: actual aspects from physiology and disease.
      ]. Glycogen breakdown is catalyzed by glycogen phosphorylase (PYGL), which cleaves glucose from the glycogen polymer and produces glucose-1-phosphate, which is converted to glucose-6-phosphate by phosphoglucomutase. A debranching enzyme cleaves the last four glucose monomers. PYGL is regulated through allosteric activation by AMP and via phosphorylation by PKA, which is inhibited by insulin.
      Figure thumbnail fx4

      Hepatic lipid and glucose metabolism in liver injury

      Serum FFA levels correlate with hepatocyte apoptosis and FAs were found to activate death receptor-mediated apoptosis [
      • Feldstein A.E.
      • Canbay A.
      • Guicciardi M.E.
      • Higuchi H.
      • Bronk S.F.
      • Gores G.J.
      Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice.
      ,
      • Bechmann L.P.
      • Gieseler R.K.
      • Sowa J.P.
      • Kahraman A.
      • Erhard J.
      • Wedemeyer I.
      • et al.
      Apoptosis is associated with CD36/fatty acid translocase upregulation in non-alcoholic steatohepatitis.
      ]. On the other hand, high glucose concentrations induce apoptosis in hepatoma cell lines, and the HOMA score is associated with hepatocyte apoptosis in NAFLD patients [
      • Chandrasekaran K.
      • Swaminathan K.
      • Chatterjee S.
      • Dey A.
      Apoptosis in HepG2 cells exposed to high glucose.
      ,
      • Civera M.
      • Urios A.
      • Garcia-Torres M.L.
      • Ortega J.
      • Martinez-Valls J.
      • Cassinello N.
      • et al.
      Relationship between insulin resistance, inflammation and liver cell apoptosis in patients with severe obesity.
      ]. These observations indicate that hepatocyte apoptosis due to an imbalance in cell metabolism has clinical implications for NAFLD, liver regeneration, as well as fibrogenesis and carcinogenesis. The effects of systemic IR on liver injury via induction of TNFα are discussed in detail below. Intrahepatic fat deposition and obesity decrease hepatic blood flow by direct compression and systemic hypercatecholemia and thus inhibit mitochondrial function and cause formation of ROS, which induces Kupffer cell activation, hepatic inflammation, and hepatocyte apoptosis [
      • Sato N.
      Central role of mitochondria in metabolic regulation of liver pathophysiology.
      ]. Interestingly, mitochondrial stress may be partially reversed by treatment with insulin-like-growth factor 1 (IGF-1) and PPARγ agonists [
      • Puche J.E.
      • Garcia-Fernandez M.
      • Muntane J.
      • Rioja J.
      • Gonzalez-Baron S.
      • Castilla Cortazar I.
      Low doses of insulin-like growth factor-I induce mitochondrial protection in aging rats.
      ,
      • Wang X.
      • Wang Z.
      • Liu J.Z.
      • Hu J.X.
      • Chen H.L.
      • Li W.L.
      • et al.
      Double antioxidant activities of rosiglitazone against high glucose-induced oxidative stress in hepatocyte.
      ]. Alcohol-fed PPARα knock-out mice develop a phenotype that mimics alcoholic liver disease in humans, which is linked to ROS accumulation [
      • Okiyama W.
      • Tanaka N.
      • Nakajima T.
      • Tanaka E.
      • Kiyosawa K.
      • Gonzalez F.J.
      • et al.
      Polyenephosphatidylcholine prevents alcoholic liver disease in PPARalpha-null mice through attenuation of increases in oxidative stress.
      ]. Overexpression studies identified that the expression of PEPCK links mitochondrial dysfunction with the ER stress response [
      • Lim J.H.
      • Lee H.J.
      • Ho Jung M.
      • Song J.
      Coupling mitochondrial dysfunction to endoplasmic reticulum stress response: a molecular mechanism leading to hepatic insulin resistance.
      ].
      As mitochondria are the main organelles in energy combustion, the ER is the major site of protein folding and trafficking. Recently, activation of the unfolded protein response (UPR) within the ER has been implied as a key modulator of cellular inflammation and is linked to IR, lipid and glucose metabolism [
      • Hotamisligil G.S.
      Endoplasmic reticulum stress and the inflammatory basis of metabolic disease.
      ]. Three membrane-bound proteins regulate the UPR within the ER; PKR-like eukaryotic initiation factor 2α kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor-6 (ATF6). The protein kinase PERK affects transcriptional regulation of rRNA, which activates NFκB and ATF4 signaling. NFκB regulates inflammatory signaling (IL-6, TNFα), and ATF4 regulates glucose metabolism [
      • Jiang H.Y.
      • Wek S.A.
      • McGrath B.C.
      • Scheuner D.
      • Kaufman R.J.
      • Cavener D.R.
      • et al.
      Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is required for activation of NF-kappaB in response to diverse cellular stresses.
      ,
      • Seo J.
      • Fortuno 3rd, E.S.
      • Suh J.M.
      • Stenesen D.
      • Tang W.
      • Parks E.J.
      • et al.
      Atf4 regulates obesity, glucose homeostasis, and energy expenditure.
      ]. SREBP-1c activation occurs during ER stress and thus affects the lipid metabolism – and the ER possibly regulates the number, composition and quality of lipid droplets [
      • Kammoun H.L.
      • Chabanon H.
      • Hainault I.
      • Luquet S.
      • Magnan C.
      • Koike T.
      • et al.
      GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice.
      ,
      • Rutkowski D.T.
      • Wu J.
      • Back S.H.
      • Callaghan M.U.
      • Ferris S.P.
      • Iqbal J.
      • et al.
      UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators.
      ,
      • Gregor M.G.
      • Hotamisligil G.S.
      Adipocyte stress: the endoplasmic reticulum and metabolic disease.
      ]. Furthermore, induction of the mTOR pathway in obese individuals activates SREBP-1c, promotes ER stress and inhibits autophagy, a novel pathway in the biology of hepatic lipid droplets [
      • Porstmann T.
      • Santos C.R.
      • Griffiths B.
      • Cully M.
      • Wu M.
      • Leevers S.
      • et al.
      SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth.
      ,
      • Jung C.H.
      • Ro S.H.
      • Cao J.
      • Otto N.M.
      • Kim D.H.
      mTOR regulation of autophagy.
      ].

      NAFLD, insulin resistance and lipotoxicity

      NAFLD represents the most prevalent liver disease in Western societies. It presents with a wide spectrum ranging from simple steatosis or non-alcoholic fatty liver (NAFL) to fully developed NASH with or without fibrosis. NASH can progress to fibrosis with an increased risk to develop end-stage liver disease or hepatocellular carcinoma (HCC) [
      • Feldstein A.E.
      Novel insights into the pathophysiology of nonalcoholic fatty liver disease.
      ]. Hepatic steatosis is defined as an intrahepatic accumulation of TAGs. In parallel, abundant FAs cause lipotoxicity via the induction of ROS release, which causes inflammation, apoptosis, and thus the progression to NASH and fibrogenesis [
      • Cheung O.
      • Sanyal A.J.
      Abnormalities of lipid metabolism in nonalcoholic fatty liver disease.
      ]. As described above, most FAs derive from the circulation secondary to increased lipolysis in adipose tissue as well as DNL [
      • Donnelly K.L.
      • Smith C.I.
      • Schwarzenberg S.J.
      • Jessurun J.
      • Boldt M.D.
      • Parks E.J.
      Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
      ].
      Obesity increases the TNFα production in adipocytes, which facilitates adipocyte IR and increases lipolysis rate [
      • Hotamisligil G.S.
      Inflammation and metabolic disorders.
      ]. Thus, the circulating FFA pool is increased in obese individuals and accounts for the majority of liver lipids in NAFLD [
      • Savage D.B.
      • Semple R.K.
      Recent insights into fatty liver, metabolic dyslipidaemia and their links to insulin resistance.
      ]. As mentioned, uptake of FFAs into the hepatocyte is facilitated by a variety of FATPs; several studies found an upregulation of these transporters in NAFLD and NASH as well as a correlation with disease severity [
      • Bechmann L.P.
      • Gieseler R.K.
      • Sowa J.P.
      • Kahraman A.
      • Erhard J.
      • Wedemeyer I.
      • et al.
      Apoptosis is associated with CD36/fatty acid translocase upregulation in non-alcoholic steatohepatitis.
      ,
      • Bieghs V.
      • Wouters K.
      • van Gorp P.J.
      • Gijbels M.J.
      • de Winther M.P.
      • Binder C.J.
      • et al.
      Role of scavenger receptor A and CD36 in diet-induced nonalcoholic steatohepatitis in hyperlipidemic mice.
      ,
      • Berk P.D.
      • Zhou S.
      • Bradbury M.W.
      Increased hepatocellular uptake of long chain fatty acids occurs by different mechanisms in fatty livers due to obesity or excess ethanol use, contributing to development of steatohepatitis in both settings.
      ]. Fifteen percent of the lipid content within the steatotic liver derives from an increased dietary intake of lipids [
      • Donnelly K.L.
      • Smith C.I.
      • Schwarzenberg S.J.
      • Jessurun J.
      • Boldt M.D.
      • Parks E.J.
      Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
      ]. DNL may account for up to 30% of TAGs in steatotic livers, a mechanism that involves dysregulation in SREBP-1c- and FoxO-mediated hepatic insulin signaling [
      • Postic C.
      • Girard J.
      Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance. lessons from genetically engineered mice.
      ,
      • Sajan M.P.
      • Standaert M.L.
      • Rivas J.
      • Miura A.
      • Kanoh Y.
      • Soto J.
      • et al.
      Role of atypical protein kinase C in activation of sterol regulatory element binding protein-1c and nuclear factor kappa B (NFkappaB) in liver of rodents used as a model of diabetes, and relationships to hyperlipidaemia and insulin resistance.
      ,
      • Taniguchi C.M.
      • Kondo T.
      • Sajan M.
      • Luo J.
      • Bronson R.
      • Asano T.
      • et al.
      Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta.
      ]. Since autophagy-related genes are transcriptionally activated by FoxO and insulin action modulates autophagy, recent studies showed that macroautophagy is dysregulated in the metabolic syndrome [
      • Liu H.Y.
      • Han J.
      • Cao S.Y.
      • Hong T.
      • Zhuo D.
      • Shi J.
      • et al.
      Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin.
      ]. Accordingly, in conditional atg7-knockout mice, Singh et al. observed an increase in hepatic lipid accumulation, and in genetic and dietary mouse models for obesity and hepatic steatosis, autophagy-related genes were downregulated [
      • Singh R.
      • Kaushik S.
      • Wang Y.
      • Xiang Y.
      • Novak I.
      • Komatsu M.
      • et al.
      Autophagy regulates lipid metabolism.
      ,
      • Yang L.
      • Li P.
      • Fu S.
      • Calay E.S.
      • Hotamisligil G.S.
      Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance.
      ].
      The long-lasting paradigm claiming TAG accumulation to be the “first hit“ that predisposes to further liver damage in the pathogenesis of NASH has recently been replaced by a more complex model as emerging evidence points to FAs and their metabolites as the true lipotoxic agents [
      • Neuschwander-Tetri B.A.
      Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites.
      ]. Interestingly, lipid accumulation and altered composition of phospholipids within ER membranes further promotes ER stress and IR in obese mice [
      • Fu S.
      • Yang L.
      • Li P.
      • Hofmann O.
      • Dicker L.
      • Hide W.
      • et al.
      Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity.
      ]. Cytosolic TAGs are thus now considered to be inert and, in fact, lipid droplet accumulation has recently been found to be hepatoprotective [
      • Ricchi M.
      • Odoardi M.R.
      • Carulli L.
      • Anzivino C.
      • Ballestri S.
      • Pinetti A.
      • et al.
      Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes.
      ]. Notably, genetic deletion of DGAT2 (responsible for TAG formation) increases hepatocellular injury in MCD-fed mice despite a reduction in the content of hepatocellular TAGs [
      • Yamaguchi K.
      • Yang L.
      • McCall S.
      • Huang J.
      • Yu X.X.
      • Pandey S.K.
      • et al.
      Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis.
      ]. However, TAG accumulation and lipid droplet formation accompany and parallel pathophysiologic mechanisms in NASH. FFAs are thus now in the focus of basic research – and FAs as well as acyl-CoA and acetyl-CoA have been identified as potential causes of lipotoxicity [
      • Han M.S.
      • Park S.Y.
      • Shinzawa K.
      • Kim S.
      • Chung K.W.
      • Lee J.H.
      • et al.
      Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes.
      ]. FAs have been found to activate Toll-like receptors and initiate the extrinsic apoptosis cascade [
      • Fessler M.B.
      • Rudel L.L.
      • Brown J.M.
      Toll-like receptor signaling links dietary fatty acids to the metabolic syndrome.
      ,
      • Feldstein A.E.
      • Werneburg N.W.
      • Canbay A.
      • Guicciardi M.E.
      • Bronk S.F.
      • Rydzewski R.
      • et al.
      Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway.
      ]. FAs also interfere with NR signaling, which might additionally influence the extent of hepatocyte damage and further promote IR and ER stress [
      • Nolan C.J.
      • Larter C.Z.
      Lipotoxicity: why do saturated fatty acids cause and monounsaturates protect against it?.
      ,
      • Erbay E.
      • Babaev V.R.
      • Mayers J.R.
      • Makowski L.
      • Charles K.N.
      • Snitow M.E.
      • et al.
      Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis.
      ]. Accordingly, β-oxidation of LCFA within peroxisomes and ω-oxidation within the ER are upregulated in NASH and contribute to lipotoxicity and ROS formation [
      • Robertson G.
      • Leclercq I.
      • Farrell G.C.
      Nonalcoholic steatosis and steatohepatitis. II. Cytochrome P-450 enzymes and oxidative stress.
      ,
      • Kohjima M.
      • Enjoji M.
      • Higuchi N.
      • Kato M.
      • Kotoh K.
      • Yoshimoto T.
      • et al.
      Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease.
      ]. This might be secondary to inhibition of mitochondrial β-oxidation due to an accumulation of malonyl-CoA and the inhibition of CPT1 [
      • Donnelly K.L.
      • Smith C.I.
      • Schwarzenberg S.J.
      • Jessurun J.
      • Boldt M.D.
      • Parks E.J.
      Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
      ,
      • Dentin R.
      • Benhamed F.
      • Hainault I.
      • Fauveau V.
      • Foufelle F.
      • Dyck J.R.
      • et al.
      Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice.
      ,
      • Tamura S.
      • Shimomura I.
      Contribution of adipose tissue and de novo lipogenesis to nonalcoholic fatty liver disease.
      ]. In fact, recent studies indicate that activation of mitochondrial FA oxidation protects from steatosis and IR [
      • Orellana-Gavalda J.M.
      • Herrero L.
      • Malandrino M.I.
      • Paneda A.
      • Sol Rodriguez-Pena M.
      • Petry H.
      • et al.
      Molecular therapy for obesity and diabetes based on a long-term increase in hepatic fatty-acid oxidation.
      ,
      • Rosselli M.S.
      • Burgueno A.L.
      • Pirola C.J.
      • Sookoian S.
      Cyclooxygenase inhibition Up-regulates liver carnitine palmitoyltransferase 1A expression and improves fatty liver.
      ]. As mentioned above, DAGs and ceramides might as well contribute to hepatocyte damage and IR in NAFLD [
      • Neuschwander-Tetri B.A.
      Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites.
      ].
      These stressors induce a variety of intracellular and paracrine mechanisms that may promote hepatocellular damage. FAs induce the production of TNFα, and hepatic TNF receptor expression correlates with the disease severity in NAFLD [
      • Crespo J.
      • Cayon A.
      • Fernandez-Gil P.
      • Hernandez-Guerra M.
      • Mayorga M.
      • Dominguez-Diez A.
      • et al.
      Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients.
      ]. TNF receptor activation increases expression of SREBP-1c, which induces hepatic lipogenesis and lipid accumulation [
      • Endo M.
      • Masaki T.
      • Seike M.
      • Yoshimatsu H.
      TNF-alpha induces hepatic steatosis in mice by enhancing gene expression of sterol regulatory element binding protein-1c (SREBP-1c).
      ]. As TNFα-mediated effects are antagonized by adiponectin, adiponectin receptors are actually downregulated in NASH [
      • Kaser S.
      • Moschen A.
      • Cayon A.
      • Kaser A.
      • Crespo J.
      • Pons-Romero F.
      • et al.
      Adiponectin and its receptors in non-alcoholic steatohepatitis.
      ]. TNFα activation is further paralleled by death-receptor expression, which facilitates activation of the extrinsic apoptosis cascade. Apoptosis indeed is the predominant form of hepatocellular injury in NASH [
      • Feldstein A.E.
      • Canbay A.
      • Guicciardi M.E.
      • Higuchi H.
      • Bronk S.F.
      • Gores G.J.
      Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice.
      ,
      • Feldstein A.E.
      • Canbay A.
      • Angulo P.
      • Taniai M.
      • Burgart L.J.
      • Lindor K.D.
      • et al.
      Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.
      ]. In fact, apoptotic activity within the diseased liver correlates with disease severity and thus cleaved cytokeratin-18 fragments in the serum of NAFLD could effectively be utilized as surrogate markers for the progression of NAFLD [
      • Feldstein A.E.
      • Wieckowska A.
      • Lopez A.R.
      • Liu Y.C.
      • Zein N.N.
      • McCullough A.J.
      Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study.
      ]. As previously mentioned, FA accumulation also leads to induction of ER stress and ROS formation, which again promotes hepatic injury [
      • Feldstein A.E.
      Novel insights into the pathophysiology of nonalcoholic fatty liver disease.
      ,
      • Horoz M.
      • Bolukbas C.
      • Bolukbas F.F.
      • Sabuncu T.
      • Aslan M.
      • Sarifakiogullari S.
      • et al.
      Measurement of the total antioxidant response using a novel automated method in subjects with nonalcoholic steatohepatitis.
      ].
      In summary, while hepatic TAG accumulation seems to be a benign symptom of hepatic steatosis, FA metabolites contribute to the progression of NAFLD to NASH. IR promotes the recruitment of FFAs from the serum pool as well as intrahepatic FA accumulation, which induces apoptosis and ROS formation. FAs themselves also promote hepatic IR via TNF receptor activation, hence indicating a vicious circle of lipid accumulation and IR as a crucial mechanism in the pathogenesis of NASH (Fig. 1D).

      Acute liver injury and regeneration

      Injured livers produce cytokine signals that trigger adipose tissue to release FAs into the circulation. Indeed, in the acute response, hepatocytes initiate the transcription of lipogenic genes and accumulate TAGs in intracellular lipid droplets. In liver regeneration (e.g., after partial hepatectomy (PHx)), lipid droplet formation is essential to propagate the proliferative response by sufficiently supplying the organ’s energy household. Droplet-stored lipids are also used for synthesizing new lipoproteins, bile acids, and entire membranes [
      • Huang W.
      • Ma K.
      • Zhang J.
      • Qatanani M.
      • Cuvillier J.
      • Liu J.
      • et al.
      Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration.
      ,
      • Fernandez M.A.
      • Albor C.
      • Ingelmo-Torres M.
      • Nixon S.J.
      • Ferguson C.
      • Kurzchalia T.
      • et al.
      Caveolin-1 is essential for liver regeneration.
      ]. As previously mentioned, emerging data supports a close connection between BA and FA metabolism. In this context, FATP-5 has also been suggested to participate in BA metabolism as a bile acid-CoA ligase [
      • Doege H.
      • Baillie R.A.
      • Ortegon A.M.
      • Tsang B.
      • Wu Q.
      • Punreddy S.
      • et al.
      Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis.
      ,
      • Hubbard B.
      • Doege H.
      • Punreddy S.
      • Wu H.
      • Huang X.
      • Kaushik V.K.
      • et al.
      Mice deleted for fatty acid transport protein 5 have defective bile acid conjugation and are protected from obesity.
      ]. FATP-5 is expressed preferentially towards the space of Disse and closely follows the hepatic sinusoids [
      • Doege H.
      • Baillie R.A.
      • Ortegon A.M.
      • Tsang B.
      • Wu Q.
      • Punreddy S.
      • et al.
      Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis.
      ] where FAs and BAs are absorbed from the enterohepatic circulation. Intriguingly, it has been recently shown that elevated BAs accelerate liver regeneration after PHx by bile acid receptor (FXR)-dependent signals [
      • Huang W.
      • Ma K.
      • Zhang J.
      • Qatanani M.
      • Cuvillier J.
      • Liu J.
      • et al.
      Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration.
      ,
      • Geier A.
      • Trautwein C.
      Bile acids are “homeotrophic” sensors of the functional hepatic capacity and regulate adaptive growth during liver regeneration.
      ].
      Autophagy in acute liver injury might to a certain degree act hepatoprotectively as it rapidly supplies the hepatocyte with energy. However, hyperactivation of autophagy induces cell death, and the necrosis rate is actually a predictor of liver failure [
      • Rautou P.E.
      • Mansouri A.
      • Lebrec D.
      • Durand F.
      • Valla D.
      • Moreau R.
      Autophagy in liver diseases.
      ,
      • Bechmann L.P.
      • Jochum C.
      • Kocabayoglu P.
      • Sowa J.P.
      • Kassalik M.
      • Gieseler R.K.
      • et al.
      Cytokeratin 18-based modification of the MELD score improves prediction of spontaneous survival after acute liver injury.
      ]. Furthermore, as we previously elucidated key processes in the interplay between adipose tissue and the liver, adiponectin was identified as an important mediator of STAT3 signaling in the regenerating liver [
      • Shu R.Z.
      • Zhang F.
      • Wang F.
      • Feng D.C.
      • Li X.H.
      • Ren W.H.
      • et al.
      Adiponectin deficiency impairs liver regeneration through attenuating STAT3 phosphorylation in mice.
      ,
      • Wree A.
      • Kahraman A.
      • Gerken G.
      • Canbay A.
      Obesity affects the liver - the link between adipocytes and hepatocytes.
      ].

      Liver cancer

      Emerging data supports a role for lipid and glucose metabolism in hepatocellular carcinogenesis [
      • Hirsch H.A.
      • Iliopoulos D.
      • Joshi A.
      • Zhang Y.
      • Jaeger S.A.
      • Bulyk M.
      • et al.
      A transcriptional signature and common gene networks link cancer with lipid metabolism and diverse human diseases.
      ]. First of all, the increase in the prevalence of NAFLD is closely associated with the development of cirrhosis and NASH-related HCC [
      • Petta S.
      • Craxi A.
      Hepatocellular carcinoma and non-alcoholic fatty liver disease: from a clinical to a molecular association.
      ]. Accordingly, NASH might account for the majority of HCC in the context of a cryptogenic cirrhosis [
      • Bugianesi E.
      Non-alcoholic steatohepatitis and cancer.
      ]. Obesity and diabetes have been identified as independent risk factors for developing HCC (Fig. 3A) [
      • Calle E.E.
      • Rodriguez C.
      • Walker-Thurmond K.
      • Thun M.J.
      Overweight, obesity and mortality from cancer in a prospectively studied cohort of U.S. adults.
      ,
      • Davila J.A.
      • Morgan R.O.
      • Shaib Y.
      • McGlynn K.A.
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      ]. Several studies could recently dissect the effects of individual confounders of the metabolic syndrome and clearly demonstrate a significant risk for NAFLD patients to develop HCC [
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      ]. Mechanistically, mediators and signaling cascades involved in the hepatic IR and the regulation of hepatic lipid metabolism are in the focus of HCC research. Several studies identified the insulin receptor downstream targets PI3-kinase/Akt and IRS to be activated in HCC when compared to surrounding healthy tissue, which mediates GSK3b phosphorylation and mTOR activation [
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      ]. As pointed out before, TNFα induces hepatic IR and thus promotes lipid accumulation. TNF and IL-6 signaling is also involved in the activation of the JAK/STAT and ERK pathways; both mediators are crucial for the development of obesity induced-HCC in a rodent model [
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      ]. On the other hand, JAK/STAT signaling is closely linked to, and partially modulated by, the adipocytokines leptin and adiponectin [
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      ].
      NRs play a crucial role in hepatic lipid and glucose homeostasis (see also above) and are important mediators of hepatic carcinogenesis. PPARα mediates hepatic FA-oxidation and transport as well as Akt phosphorylation via its downstream target TRB-3 [
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      ]. PPARα agonists promote carcinogenesis in a rodent model for HCV infection [
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      PPARalpha activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice.
      ]. Interestingly, PPARα agonists not only interfere with the binding of PPARα to SREBP-1c, but also with STAT3 in hepatoma cell lines, thus indicating a potential mechanism for its carcinogenic properties [
      • van der Meer D.L.
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      ]. In contrast, PPARγ agonists prevent NAFLD progression and, more interestingly, were in some studies described to act antineoplastically [
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      • Charlotte F.
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      • et al.
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      ,
      • Yu J.
      • Qiao L.
      • Zimmermann L.
      • Ebert M.P.
      • Zhang H.
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      Troglitazone inhibits tumor growth in hepatocellular carcinoma in vitro and in vivo.
      ]. Notably, the majority of mechanistical data in hepatic carcinogenesis derives from hepatoma cell lines and murine models that are only of limited value for the elucidation of hepatic carcinogenesis in humans.

      Conclusions

      Hepatic lipid and glucose metabolism are closely interrelated with inflammatory, proliferative and apoptotic signaling within the liver. In the liver, these catabolic and anabolic pathways can hardly be separated. They share intermediate metabolites and receptor signaling, and go hand in hand in the pathogenesis of the most common liver diseases. Intriguingly, the case that these metabolic pathways are also involved in cell proliferation, regeneration and carcinogenesis implies potent future therapeutic approaches for life-threatening diseases. The enhanced understanding of these basic mechanisms is thus imperative as we witness a rising prevalence of obesity and the metabolic syndrome.

      Conflict of interest

      The authors do not have a relationship with the manufacturers of the drugs involved either in the past or present and did not receive funding from the manufacturers to carry out their research. The authors received support from DFG, Wilhelm Laupitz Foundation, EASL, and IFORES.

      Financial support

      AC is supported by the Deutsche Forschungsgemeinschaft (DFG, grant 267/6-1 and 267/8-1), and the Wilhelm Laupitz Foundation. LPB is supported by an EASL Sheila Sherlock short-term fellowship and the IFORES Program of the University of Duisburg-Essen.

      Acknowledgements

      The authors would like to thank Robert Gieseler von der Crone, Jan-Peter Sowa, Judith Ertle and Thomas Schreiter for instructive discussions and careful review of this manuscript.

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