Reprogramming metabolism of HSCs drives their fibrogenic/immunoregulator functions
Glycolysis drives HSC activation
Glutaminolysis supports HSC activation
Lipid metabolism directs activation of HSCs
|SLGT1/2 inhibitor||Empaglifozin||Phase II/III||Decrease hepatic fat.|
|Licoglifozin||Phase II||Significant improvement of liver stiffness|
A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: design of the NATIVE study.
Contemp Clin Trials. 2020; 98: 106170
|Phase II||[No significant decrease in fibrosis (Harrison S AASLD: Boston, MA, USA, 2019)]|
|Hexokinase inhibitor||PF-06835919||Phase IIa||Recruiting|
|ACC1&2 inhibitor||Firsocostat||Phase II||30% reduction of liver fat.|
|Decrease in the fibrosis marker TIMP-1. No decrease in ELF test and magnetic resonance elastography|
|SCD1 inhibitor||Aramchol||Phase IIb||Reduction in fibrosis at 600 mg without worsening of NASH [Ratziu V, AASLD, San Francisco, USA 2018]|
|PPAR||Lanifibranor (α/β/γ)||Phase II||Resolution of NASH with no worsening of fibrosis|
|Saroglitazar (α&γ)||Phase II||Improvement of liver biochemistry and steatosis. Decrease in APRI and ELF. No clear decrease in liver stiffness [Gawrieh S AASLD: Boston MA, USA, 2019]|
|Elafibranor (α&δ)||Phase III||Not superior to placebo for fibrosis|
|Seladelpar (δ)||Phase II||Suspended for unexpected effects|
|FXR agonist||Tropifexor||Phase II||Decrease in steatosis and in ALT. Results on liver biopsies expected|
|Obeticholic Acid||Phase III||Improve fibrosis w/o NASH worsening|
|Mitochondrial pyruvate carrier|
|MPC inhibitor||MSDC-0602K||Phase IIb|
|Reduction in glucose liver enzymes. No improvement of fibrosis|
|ASK1 inhibitor||Selonsertib||Phase III||Not superior to placebo|
|AMPK & PG1Ca||Resveratrol||Phase II/III||Prevents liver damage|
Targeting cholesterol metabolism
Immunometabolic regulation of liver fibrosis
Macrophage cell metabolism and fibrogenesis
Accumulation of lipids in Kupffer cells is proinflammatory
Targeting lipid metabolism in macrophages: A role for monoacylglycerols
Targeting acetoacetate metabolism: a two-tale hepatocyte-macrophage story
Metabolism of adaptive immune cells and innate/innate-like lymphoid cells and liver fibrosis
Hepatocyte metabolism and liver fibrosis
- Thangapandi V.R.
- Knittelfelder O.
- Brosch M.
- Patsenker E.
- Vvedenskaya O.
- Buch S.
- et al.
Targeting common metabolic pathways in different liver cell types: Benefits and pitfalls
- Du K.
- Oh S.
- Sun T.
- Yang W.-H.
- Chi J.
- Diehl A.
- Zhong L.
- Ning B.
- Du X.
- Huang S.
- Cai C.
- Zhou Y.
- et al.
- Francke S.
- Bedossa P.
- Abdelmalek M.
- Quentin Anstee M.
- Bugianesi E.
- Vlad R.
- et al.
Targeting cell intrinsic metabolism for antifibrotic therapy – clinical perspectives
- Francke S.
- Bedossa P.
- Abdelmalek M.
- Quentin Anstee M.
- Bugianesi E.
- Vlad R.
- et al.
- Pedrosa M.
- Seyedkazemi S.
- Francque S.
- Sanyal A.
- Rinella M.
- Charlton M.
- et al.
Towards cell-specific metabolic targeting of antifibrotic agents
Conflict of interest
- Multimedia component 1
- Hepatic fibrosis: molecular mechanisms and drug targets.Annu Rev Pharmacol Toxicol. 2005; 45: 605-628
- Cellular mechanisms of tissue fibrosis. 5. Novel insights into liver fibrosis.Am J Physiol Cell Physiol. 2013; 305: C789-C799
- Pathophysiology of NASH: perspectives for a targeted treatment.Curr Pharm Des. 2013; 19: 5250-5269
- Mechanisms of hepatic stellate cell activation.Nat Rev Gastroenterol Hepatol. 2017; 14: 397-411
- Origins and functions of liver myofibroblasts.Biochim Biophys Acta. 2013; 1832: 948-954
- Mechanisms of fibrosis development in nonalcoholic steatohepatitis.Gastroenterology. 2020; 158: 1913-1928
- Liver inflammation and fibrosis.J Clin Invest. 2017; 127: 55-64
- Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis.Nat Metab. 2019; 1: 147-157
- Hexokinase 2 couples glycolysis with the profibrotic actions of TGF-beta.Sci Signal. 2019; 12: 4067
- Targeting metabolic dysregulation for fibrosis therapy.Nat Rev Drug Discov. 2020; 19: 57-75
- Hedgehog controls hepatic stellate cell fate by regulating metabolism.Gastroenterology. 2012; 143: 1319-1329
- CPEB4 increases expression of PFKFB3 to induce glycolysis and activate mouse and human hepatic stellate cells, promoting liver fibrosis.Gastroenterology. 2020; 159: 273-288
- Pyruvate kinase M2 tetramerization protects against hepatic stellate cell activation and liver fibrosis.Am J Pathol. 2020; 190: 2267-2281
- Hedgehog-YAP signaling pathway regulates glutaminolysis to control activation of hepatic stellate cells.Gastroenterology. 2018; 154: 1465-1479
- De novo expression of glutamine synthetase during transformation of hepatic stellate cells into myofibroblast-like cells.Biochem J. 1998; 335: 697-700
- Regulation of hepatic stellate cell proliferation and activation by glutamine metabolism.PLoS One. 2017; 12e0182679
- Increased glutaminolysis marks active scarring in nonalcoholic steatohepatitis progression.Cell Mol Gastroenterol Hepatol. 2020; 10: 1-21
- Glutamate signaling in hepatic stellate cells drives alcoholic steatosis.Cell Metab. 2019; 30: 877-889
- Glutamate signaling in alcohol-associated fatty liver: "Pas de Deux".Hepatology. 2020; 72: 350-352
- Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation.J Hepatol. 2020; 73: 896-905
- Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation.Cell Metab. 2017; 26: 394-406
- GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease.Gastroenterology. 2018; 155: 1463-1473
- Stearoyl-CoA desaturase promotes liver fibrosis and tumor development in mice via a Wnt positive-signaling loop by stabilization of low-density lipoprotein-receptor-related proteins 5 and 6.Gastroenterology. 2017; 152: 1477-1491
- Role of Aramchol in steatohepatitis and fibrosis in mice.Hepatol Commun. 2017; 1: 911-927
- Recent insights into the pathogenesis of nonalcoholic fatty liver disease.Annu Rev Pathol. 2018; 13: 321-350
- A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells.Gastroenterology. 2012; 142: 152-164
- Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells.J Hepatol. 2014; 61: 98-106
- PNPLA3 I148M variant impairs liver X receptor signaling and cholesterol homeostasis in human hepatic stellate cells.Hepatol Commun. 2019; 3: 1191-1204
- De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells.Nat Med. 2014; 20: 1327-1333
- Succinate causes alpha-SMA production through GPR91 activation in hepatic stellate cells.Biochem Biophys Res Commun. 2015; 463: 853-858
- Sirtuin 3 (SIRT3) regulates alpha-smooth muscle actin (alpha-SMA) production through the succinate dehydrogenase-G protein-coupled receptor 91 (GPR91) pathway in hepatic stellate cells.J Biol Chem. 2016; 291: 10277-10292
- SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity.Nat Immunol. 2019; 20: 581-592
- Macrophages in obesity and non-alcoholic fatty liver disease: crosstalk with metabolism.JHEP Rep. 2019; 1: 30-43
- Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis.Proc Natl Acad Sci U S A. 2012; 109: E3186-E3195
- A guide to immunometabolism for immunologists.Nat Rev Immunol. 2016; 16: 553-565
- Metabolic adaptations of tissue-resident immune cells.Nat Immunol. 2019; 20: 793-801
- Metabolic reprogramming of macrophages in atherosclerosis: is it all about cholesterol?.J Lipid Atheroscler. 2020; 9: 231-242
- Transcriptional regulation of hepatic stellate cells.Adv Drug Deliv Rev. 2009; 61: 497-512
- Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation.Liver Int. 2013; 33: 1056-1061
- Role of scavenger receptor A and CD36 in diet-induced nonalcoholic steatohepatitis in hyperlipidemic mice.Gastroenterology. 2010; 138: 2477-2486
- Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis.J Hepatol. 2012; 57: 141-149
- Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver.Gut. 2019; 68: 522-532
- Lack of monoacylglycerol lipase prevents hepatic steatosis by favoring lipid storage in adipose tissue and intestinal malabsorption.J Lipid Res. 2019; 60: 1284-1292
- Monoacylglycerol lipase inhibition protects from liver injury in mouse models of sclerosing cholangitis.Hepatology. 2020; 71: 1750-1765
- Hepatocyte-macrophage acetoacetate shuttle protects against tissue fibrosis.Cell Metab. 2019; 29: 383-398
- Hepatic inflammation and fibrosis: functional links and key pathways.Hepatology. 2015; 61: 1066-1079
- The spectrum of T cell metabolism in health and disease.Nat Rev Immunol. 2018; 18: 19-34
- The gut microbiota at the service of immunometabolism.Cell Metab. 2020; 32: 514-523
- Mucosal-associated invariant T cells are a profibrogenic immune cell population in the liver.Nat Commun. 2018; 9: 2146
- Mucosal-associated invariant T cells and disease.Nat Rev Immunol. 2019; 11: 3755
- FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome.Nat Cell Biol. 2020; 22: 728-739
- Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis.N Engl J Med. 2017; 377: 2063-2072
- Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation.Gut. 2018; 67: 963-972
- Targeting a ceramide double bond improves insulin resistance and hepatic steatosis.Science. 2019; 365: 386-392
- Targeted induction of ceramide degradation leads to improved systemic metabolism and reduced hepatic steatosis.Cell Metab. 2015; 22: 266-278
- Loss of hepatic Mboat7 leads to liver fibrosis.Gut. 2020; https://doi.org/10.1136/gutjnl-2020-320853
- A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis.Nat Genet. 2015; 47: 1443-1448
- The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent.Gastroenterology. 2016; 150: 1219-1230
- MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C.Nat Commun. 2016; 7: 12757
- The membrane-bound O-acyltransferase domain-containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B.Hepatology. 2017; 65: 1840-1850
- Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis.Hepatology. 2017; 65: 1543-1556
- Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase IIb study.J Hepatol. 2020; 72: 613-626
- Autophagy in liver diseases: time for translation?.J Hepatol. 2019; 70: 985-998
- Autophagy in chronic liver diseases: the two faces of Janus.Am J Physiol Cell Physiol. 2017; 312: C263-C273
- Autophagy: a multifaceted partner in liver fibrosis.Biomed Res Int. 2014; 2014: 869390
- Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy.J Hepatol. 2014; 61: 617-625
- A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis.J Hepatol. 2020; 72: 528-538
- Macrophage autophagy protects against liver fibrosis in mice.Autophagy. 2015; 11: 1280-1292
- LC3-associated phagocytosis protects against inflammation and liver fibrosis via immunoreceptor inhibitory signaling.Sci Transl Med. 2020; 12eaaw8523
- Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues.Gastroenterology. 2012; 142: 938-946
- A role for autophagy during hepatic stellate cell activation.J Hepatol. 2011; 55: 1353-1360
- Hepatic stellate cell autophagy inhibits extracellular vesicle release to attenuate liver fibrosis.J Hepatol. 2020; 73: 1144-1154
- Rapamycin inhibits hepatic stellate cell proliferation in vitro and limits fibrogenesis in an in vivo model of liver fibrosis.Gastroenterology. 1999; 117: 1198-1204
- An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis.Science. 2010; 329: 229-232
- Ferroptosis as a target for protection against cardiomyopathy.Proc Natl Acad Sci U S A. 2019; 116: 2672-2680
- Ferroptosis inhibitor alleviates Radiation-induced lung fibrosis (RILF) via down-regulation of TGF-beta1.J Inflamm (Lond). 2019; 16: 11
- Inhibiting xCT/SLC7A11 induces ferroptosis of myofibroblastic hepatic stellate cells and protects against liver fibrosis.bioRxiv. 2019; https://doi.org/10.1101/2019.1112.1123.886259
- P53-dependent induction of ferroptosis is required for artemether to alleviate carbon tetrachloride-induced liver fibrosis and hepatic stellate cell activation.IUBMB Life. 2019; 71: 45-56
- Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis.J Leukoc Biol. 2019; 105: 1015-1026
- Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis.Cell Death Dis. 2019; 10: 449
- Nuclear receptors, RXR, and the big bang.Cell. 2014; 157: 255-266
- Liver X receptors regulate cholesterol metabolism and immunity in hepatic nonparenchymal cells.Int J Mol Sci. 2019; 20: 5045
- Liver X receptor alpha is essential for the capillarization of liver sinusoidal endothelial cells in liver injury.Sci Rep. 2016; 6: 21309
- Liver X receptor signaling is a determinant of stellate cell activation and susceptibility to fibrotic liver disease.Gastroenterology. 2011; 140: 1052-1062
- Activation of liver X receptor/retinoid X receptor pathway ameliorates liver disease in Atp7B(-/-) (Wilson disease) mice.Hepatology. 2016; 63: 1828-1841
- Impaired LXRalpha phosphorylation attenuates progression of fatty liver disease.Cell Rep. 2019; 26 (e986): 984-995
- Liver X receptor b controls hepatic stellate cell activation via Hedgehog Signaling.bioRxiv. 2019; : 577833https://doi.org/10.1101/577833
- Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis.J Hepatol. 2009; 51: 380-388
- The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis.Gastroenterology. 2004; 127: 1497-1512
- FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis.Sci Rep. 2016; 6: 33453
- Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts.Am J Pathol. 2009; 175: 2392-2405
- Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease.J Biol Chem. 2013; 288: 11761-11770
- The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction.J Hepatol. 2017; 66: 724-733
- Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors.Nat Rev Gastroenterol Hepatol. 2021; 18: 24-39
- PPARalpha activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats.J Hepatol. 2012; 56: 1033-1039
- Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice.Hepatology. 2004; 39: 1286-1296
- Peroxisome proliferator-activated receptor gamma suppresses proximal alpha1(I) collagen promoter via inhibition of p300-facilitated NF-I binding to DNA in hepatic stellate cells.J Biol Chem. 2005; 280: 40650-40659
- Identification of lineage-specific transcription factors that prevent activation of hepatic stellate cells and promote fibrosis resolution.Gastroenterology. 2020; 158: 1728-1744
- Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro.Gastroenterology. 2002; 122: 1924-1940
- Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial.Gastroenterology. 2008; 135: 100-110
- Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial.Hepatology. 2010; 51: 445-453
- Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages.J Hepatol. 2020; 73: 757-770
- A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: design of the NATIVE study.Contemp Clin Trials. 2020; 98: 106170
- Effect of empagliflozin on liver steatosis and fibrosis in patients with non-alcoholic fatty liver disease without diabetes: a randomized, double-blind, placebo-controlled trial.Adv Ther. 2020; 37: 4697-4708
- Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.Lancet. 2019; 394: 2184-2196
- Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges.Gut. 2020; 69: 1877-1884
- Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening.Gastroenterology. 2016; 150: 1147-1159
- SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis.Nat Commun. 2020; 11: 240
- A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: study design of the TANDEM trial.Contemp Clin Trials. 2020; 88: 105889
- Targeted therapy of liver fibrosis/cirrhosis and its complications.J Hepatol. 2011; 55: 726-728
- Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice.Nucleic Acids Res. 2014; 42: 8796-8807
- Clinical proof of concept for a novel hepatocyte-targeting GalNAc-siRNA conjugate.Mol Ther. 2017; 25: 71-78
- Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice.Hepatology. 2011; 54: 586-596
- Recent advances in nanomedicine for the diagnosis and therapy of liver fibrosis.Nanomaterials (Basel). 2020; 10
- Therapeutic targeting of liver inflammation and fibrosis by nanomedicine.Hepatobiliary Surg Nutr. 2014; 3: 364-376
- Liver fibrosis affects the targeting properties of drug delivery systems to macrophage subsets in vivo.Biomaterials. 2019; 206: 49-60
- No anti-fibrotic effect of selonsertib in NASH.Nat Rev Gastroenterol Hepatol. 2020; 17: 260