Nuclear receptors in liver fibrosis

Schaffner, 1963, Capillarization of hepatic sinusoids in man, Gastroenterology, 44, 239, 10.1016/S0016-5085(63)80130-4 Kisseleva, 2021, Molecular and cellular mechanisms of liver fibrosis and its regression, Nat. Rev. Gastroenterol. Hepatol., 18, 151, 10.1038/s41575-020-00372-7 Bataller, 2005, Liver fibrosis, J. Clin. Invest., 115, 209, 10.1172/JCI24282 Friedman, 2008, Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver, Physiol. Rev., 88, 125, 10.1152/physrev.00013.2007 Reynaert, 2002, Hepatic stellate cells: role in microcirculation and pathophysiology of portal hypertension, Gut, 50, 571, 10.1136/gut.50.4.571 Mederacke, 2013, Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology, Nat. Commun., 4, 2823, 10.1038/ncomms3823 Hernandez-Gea, 2011, Pathogenesis of liver fibrosis, Annu. Rev. Pathol., 6, 425, 10.1146/annurev-pathol-011110-130246 Pinzani, 2011, Epithelial-mesenchymal transition in chronic liver disease: fibrogenesis or escape from death?, J. Hepatol., 55, 459, 10.1016/j.jhep.2011.02.001 Chen, 2020, Study on the relationship between hepatic fibrosis and epithelial-mesenchymal transition in intrahepatic cells, Biomed. Pharmacother., 129, 110413, 10.1016/j.biopha.2020.110413 Piera-Velazquez, 2011, Role of endothelial-mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders, Am. J. Pathol., 179, 1074, 10.1016/j.ajpath.2011.06.001 Ribera, 2017, A small population of liver endothelial cells undergoes endothelial-to-mesenchymal transition in response to chronic liver injury, Am. J. Physiol. Gastrointest. Liver Physiol., 313, G492, 10.1152/ajpgi.00428.2016 Pellicoro, 2012, Reversibility of liver fibrosis, Fibrogenesis Tissue Repair, 5, S26, 10.1186/1755-1536-5-S1-S26 Morcos, 1985, Reversal of hepatic fibrosis after praziquantel therapy of murine schistosomiasis, Am. J. Trop. Med. Hyg., 34, 314, 10.4269/ajtmh.1985.34.314 Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015;149:367–78 e5; quiz e14–5. Marcellin, 2013, Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study, Lancet, 381, 468, 10.1016/S0140-6736(12)61425-1 Ellis, 2012, Clinical evidence for the regression of liver fibrosis, J. Hepatol., 56, 1171, 10.1016/j.jhep.2011.09.024 Roehlen, 2020, Liver fibrosis: mechanistic concepts and therapeutic perspectives, Cells, 9 Xiao, 2005, NF-kappaB, an evolutionarily conserved mediator of immune and inflammatory responses, Adv. Exp. Med. Biol., 560, 41, 10.1007/0-387-24180-9_5 Pahl, 1999, Activators and target genes of Rel/NF-kappaB transcription factors, Oncogene, 18, 6853, 10.1038/sj.onc.1203239 Seki, 2007, TLR4 enhances TGF-beta signaling and hepatic fibrosis, Nat. Med., 13, 1324, 10.1038/nm1663 Luedde, 2011, NF-kappaB in the liver--linking injury, fibrosis and hepatocellular carcinoma, Nat. Rev. Gastroenterol. Hepatol., 8, 108, 10.1038/nrgastro.2010.213 Oakley, 2003, Basal expression of IkappaBalpha is controlled by the mammalian transcriptional repressor RBP-J (CBF1) and its activator Notch1, J. Biol. Chem., 278, 24359, 10.1074/jbc.M211051200 Mann, 2007, Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis, Cell Death Differ., 14, 275, 10.1038/sj.cdd.4401979 Elsharkawy, 2007, Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis, Hepatology, 46, 590, 10.1002/hep.21802 Zollner, 2009, Nuclear receptors as therapeutic targets in cholestatic liver diseases, Br. J. Pharmacol., 156, 7, 10.1111/j.1476-5381.2008.00030.x Wagner, 2008, Nuclear bile acid receptor farnesoid X receptor meets nuclear factor-kappaB: new insights into hepatic inflammation, Hepatology, 48, 1383, 10.1002/hep.22668 Wang, 2008, Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response, Hepatology, 48, 1632, 10.1002/hep.22519 Ogawa, 2005, Molecular determinants of crosstalk between nuclear receptors and toll-like receptors, Cell, 122, 707, 10.1016/j.cell.2005.06.029 Nuclear Receptors Nomenclature, 1999, A unified nomenclature system for the nuclear receptor superfamily, Cell, 97, 161, 10.1016/S0092-8674(00)80726-6 Laudet, 1997, Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor, J. Mol. Endocrinol., 19, 207, 10.1677/jme.0.0190207 Jin, 2010, Structural and functional insights into nuclear receptor signaling, Adv. Drug Deliv. Rev., 62, 1218, 10.1016/j.addr.2010.08.007 Arrese, 2010, Nuclear receptors, inflammation, and liver disease: insights for cholestatic and fatty liver diseases, Clin. Pharmacol. Ther., 87, 473, 10.1038/clpt.2010.2 Weatherman, 1999, Nuclear-receptor ligands and ligand-binding domains, Annu. Rev. Biochem., 68, 559, 10.1146/annurev.biochem.68.1.559 Daigo, 2011, Proteomic analysis of native hepatocyte nuclear factor-4alpha (HNF4alpha) isoforms, phosphorylation status, and interactive cofactors, J. Biol. Chem., 286, 674, 10.1074/jbc.M110.154732 Shaffer, 2004, Vitamin D receptor-DNA interactions, Vitam. Horm., 68, 257, 10.1016/S0083-6729(04)68009-5 Bishop, 1997, How hormone receptor-DNA binding affects nucleosomal DNA: the role of symmetry, Biophys. J., 72, 2056, 10.1016/S0006-3495(97)78849-0 Claessens, 2004, DNA recognition by nuclear receptors, Essays Biochem., 40, 59, 10.1042/bse0400059 Khorasanizadeh, 2001, Nuclear-receptor interactions on DNA-response elements, Trends Biochem. Sci., 26, 384, 10.1016/S0968-0004(01)01800-X Kobayashi, 2008, DNA-binding profiling of human hormone nuclear receptors via fluorescence correlation spectroscopy in a cell-free system, FEBS Lett., 582, 2737, 10.1016/j.febslet.2008.07.003 Mangelsdorf, 1995, The nuclear receptor superfamily: the second decade, Cell, 83, 835, 10.1016/0092-8674(95)90199-X Sever R, Glass CK. Signaling by nuclear receptors. Cold Spring Harb Perspect Biol 2013;5:a016709. Glass, 2000, The coregulator exchange in transcriptional functions of nuclear receptors, Genes Dev., 14, 121, 10.1101/gad.14.2.121 Bulynko, 2011, Nuclear receptor coactivators: structural and functional biochemistry, Biochemistry, 50, 313, 10.1021/bi101762x Unsworth, 2018, Non-genomic effects of nuclear receptors: insights from the anucleate platelet, Cardiovasc. Res., 114, 645, 10.1093/cvr/cvy044 Tran, 2018, Nuclear receptors and liver disease: summary of the 2017 basic research symposium, Hepatol. Commun., 2, 765, 10.1002/hep4.1203 Otte, 2003, Identification of farnesoid X receptor beta as a novel mammalian nuclear receptor sensing lanosterol, Mol. Cell. Biol., 23, 864, 10.1128/MCB.23.3.864-872.2003 Wang, 2008, FXR: a metabolic regulator and cell protector, Cell Res., 18, 1087, 10.1038/cr.2008.289 Han, 2018, Update on FXR biology: promising therapeutic target?, Int. J. Mol. Sci., 19 Lee, 2006, FXR, a multipurpose nuclear receptor, Trends Biochem. Sci., 31, 572, 10.1016/j.tibs.2006.08.002 Ding, 2015, Bile acid nuclear receptor FXR and digestive system diseases, Acta Pharm. Sin. B, 5, 135, 10.1016/j.apsb.2015.01.004 Thomas, 2008, Targeting bile-acid signalling for metabolic diseases, Nat. Rev. Drug Discov., 7, 678, 10.1038/nrd2619 Li, 2007, Farnesoid x receptor ligands inhibit vascular smooth muscle cell inflammation and migration, Arterioscler. Thromb. Vasc. Biol., 27, 2606, 10.1161/ATVBAHA.107.152694 Fuchs, 2016, Liver capsule: FXR agonists against liver disease, Hepatology, 64, 1773, 10.1002/hep.28836 Kok, 2003, Enterohepatic circulation of bile salts in farnesoid X receptor-deficient mice: efficient intestinal bile salt absorption in the absence of ileal bile acid-binding protein, J. Biol. Chem., 278, 41930, 10.1074/jbc.M306309200 Yang, 2007, Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor, Cancer Res., 67, 863, 10.1158/0008-5472.CAN-06-1078 Huang, 2006, Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration, Science, 312, 233, 10.1126/science.1121435 Fickert, 2009, 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., 175, 2392, 10.2353/ajpath.2009.090114 Kong, 2009, Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet, J. Pharmacol. Exp. Ther., 328, 116, 10.1124/jpet.108.144600 Wu, 2015, Excessive bile acid activated NF-kappa B and promoted the development of alcoholic steatohepatitis in farnesoid X receptor deficient mice, Biochimie, 115, 86, 10.1016/j.biochi.2015.05.014 Baghdasaryan, 2011, Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2−/− (Abcb4−/−) mouse cholangiopathy model by promoting biliary HCO(−)(3) output, Hepatology, 54, 1303, 10.1002/hep.24537 Fiorucci, 2004, The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis, Gastroenterology, 127, 1497, 10.1053/j.gastro.2004.08.001 Fiorucci, 2005, A farnesoid x receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis, J. Pharmacol. Exp. Ther., 314, 584, 10.1124/jpet.105.084905 Park, 2008, Loss of orphan receptor small heterodimer partner sensitizes mice to liver injury from obstructive cholestasis, Hepatology, 47, 1578, 10.1002/hep.22196 Renga, 2011, SHP-dependent and -independent induction of peroxisome proliferator-activated receptor-gamma by the bile acid sensor farnesoid X receptor counter-regulates the pro-inflammatory phenotype of liver myofibroblasts, Inflamm. Res., 60, 577, 10.1007/s00011-010-0306-1 Cipriani, 2017, Decoding the role of the nuclear receptor SHP in regulating hepatic stellate cells and liver fibrogenesis, Sci. Rep., 7, 41055, 10.1038/srep41055 Li, 2011, Roles of microRNA-29a in the antifibrotic effect of farnesoid X receptor in hepatic stellate cells, Mol. Pharmacol., 80, 191, 10.1124/mol.110.068247 Li, 2010, Inhibition of endothelin-1-mediated contraction of hepatic stellate cells by FXR ligand, PLoS One, 5, 10.1371/journal.pone.0013955 Koda, 2006, Endothelin-1 enhances fibrogenic gene expression, but does not promote DNA synthesis or apoptosis in hepatic stellate cells, Comp. Hepatol., 5, 5, 10.1186/1476-5926-5-5 Schwabl, 2017, The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction, J. Hepatol., 66, 724, 10.1016/j.jhep.2016.12.005 Schwabl, 2021, The non-steroidal FXR agonist cilofexor improves portal hypertension and reduces hepatic fibrosis in a rat NASH model, Biomedicines, 9 Younossi, 2019, Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial, Lancet, 394, 2184, 10.1016/S0140-6736(19)33041-7 Kowdley, 2020, A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis, J. Hepatol., 73, 94, 10.1016/j.jhep.2020.02.033 Ratziu, 2019, REGENERATE: design of a pivotal, randomised, phase 3 study evaluating the safety and efficacy of obeticholic acid in patients with fibrosis due to nonalcoholic steatohepatitis, Contemp. Clin. Trials, 84, 105803, 10.1016/j.cct.2019.06.017 Inagaki, 2005, Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis, Cell Metab., 2, 217, 10.1016/j.cmet.2005.09.001 Schumacher, 2017, The effect of fibroblast growth factor 15 deficiency on the development of high fat diet induced non-alcoholic steatohepatitis, Toxicol. Appl. Pharmacol., 330, 1, 10.1016/j.taap.2017.06.023 Zhou, 2017, Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice, Hepatol. Commun., 1, 1024, 10.1002/hep4.1108 Harrison SA, 2020, Positive topline results from a 24-week, randomized, doubleblind, placebo-controlled, multicenter, phase 2 study of the FGF19 analogue aldafermin (NGM282) in patients with non-alcoholic steatohepatitis, J. Hepatol., 73, S99, 10.1016/S0168-8278(20)30750-9 Harrison, 2020, LBO01 - positive topline results from a 24-week, randomized, double-blind, placebo-controlled, multicenter, phase 2 study of the FGF19 analogue aldafermin (NGM282) in patients with non-alcoholic steatohepatitis, J. Hepatol., 73, S114, 10.1016/S0168-8278(20)30750-9 Hirschfield, 2019, Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial, J. Hepatol., 70, 483, 10.1016/j.jhep.2018.10.035 Vavassori, 2009, The bile acid receptor FXR is a modulator of intestinal innate immunity, J. Immunol., 183, 6251, 10.4049/jimmunol.0803978 Inagaki, 2006, Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor, Proc. Natl. Acad. Sci. U. S. A., 103, 3920, 10.1073/pnas.0509592103 Ubeda, 2016, Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats, J. Hepatol., 64, 1049, 10.1016/j.jhep.2015.12.010 Gai, 2018, Effects of farnesoid X receptor activation on arachidonic acid metabolism, NF-kB signaling, and hepatic inflammation, Mol. Pharmacol., 94, 802, 10.1124/mol.117.111047 Liu, 2018, GW4064 attenuates lipopolysaccharideinduced hepatic inflammation and apoptosis through inhibition of the Tolllike receptor 4mediated p38 mitogenactivated protein kinase signaling pathway in mice, Int. J. Mol. Med., 41, 1455 Xu, 2012, FXR ligands protect against hepatocellular inflammation via SOCS3 induction, Cell. Signal., 24, 1658, 10.1016/j.cellsig.2012.04.015 Anfuso, 2020, Obeticholic acid and INT-767 modulate collagen deposition in a NASH in vitro model, Sci. Rep., 10, 1699, 10.1038/s41598-020-58562-x Zhang, 2009, Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis, J. Hepatol., 51, 380, 10.1016/j.jhep.2009.03.025 Kinzel, 2016, Novel substituted isoxazole FXR agonists with cyclopropyl, hydroxycyclobutyl and hydroxyazetidinyl linkers: understanding and improving key determinants of pharmacological properties, Bioorg. Med. Chem. Lett., 26, 3746, 10.1016/j.bmcl.2016.05.070 Gege, 2014, Knocking on FXR’s door: the “hammerhead”-structure series of FXR agonists - amphiphilic isoxazoles with potent in vitro and in vivo activities, Curr. Top. Med. Chem., 14, 2143, 10.2174/1568026614666141112094430 Brusilovskaya, 2019, Vascular targets for the treatment of portal hypertension, Semin. Liver Dis., 39, 483, 10.1055/s-0039-1693115 Patel K, Harrison SA, Elkhashab M, et al. Cilofexor, a nonsteroidal FXR agonist, in patients with noncirrhotic NASH: A phase 2 randomized controlled trial. Hepatology 2020;72:58–71. Loomba, 2021, Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH, Hepatology, 73, 625, 10.1002/hep.31622 Bookout, 2006, Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network, Cell, 126, 789, 10.1016/j.cell.2006.06.049 Gascon-Barré, 2003, The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells, Hepatology, 37, 1034, 10.1053/jhep.2003.50176 Ding, 2013, A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response, Cell, 153, 601, 10.1016/j.cell.2013.03.028 Abramovitch, 2011, Vitamin D inhibits proliferation and profibrotic marker expression in hepatic stellate cells and decreases thioacetamide-induced liver fibrosis in rats, Gut, 60, 1728, 10.1136/gut.2010.234666 Abramovitch, 2015, Vitamin D inhibits development of liver fibrosis in an animal model but cannot ameliorate established cirrhosis, Am. J. Physiol. Gastrointest. Liver Physiol., 308, G112, 10.1152/ajpgi.00132.2013 Hochrath, 2014, Vitamin D modulates biliary fibrosis in ABCB4-deficient mice, Hepatol. Int., 8, 443, 10.1007/s12072-014-9548-2 Udomsinprasert, 2019, Vitamin D and liver fibrosis: molecular mechanisms and clinical studies, Biomed. Pharmacother., 109, 1351, 10.1016/j.biopha.2018.10.140 Norena, 2017, Calcitriol-mediated hypercalcemia secondary to granulomatous disease caused by soft-tissue filler injection: a case report, Clin. Cases Miner. Bone Metab., 14, 340, 10.11138/ccmbm/2017.14.3.340 Azevedo, 2017, Effect of vitamin D serum levels and GC gene polymorphisms in liver fibrosis due to chronic hepatitis C, Ann. Hepatol., 16, 742, 10.5604/01.3001.0010.2748 Baur, 2012, Combined effect of 25-OH vitamin D plasma levels and genetic vitamin D receptor (NR 1I1) variants on fibrosis progression rate in HCV patients, Liver Int., 32, 635, 10.1111/j.1478-3231.2011.02674.x Petta, 2013, Association of vitamin D serum levels and its common genetic determinants, with severity of liver fibrosis in genotype 1 chronic hepatitis C patients, J. Viral Hepat., 20, 486, 10.1111/jvh.12072 Hazra S, Miyahara T, Rippe RA, et al. PPAR gamma and hepatic stellate cells. Comp. Hepatol. 2004;3 Suppl 1:S7. Braissant, 1996, Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat, Endocrinology, 137, 354, 10.1210/endo.137.1.8536636 Feige, 2006, From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions, Prog. Lipid Res., 45, 120, 10.1016/j.plipres.2005.12.002 Berger, 2002, The mechanisms of action of PPARs, Annu. Rev. Med., 53, 409, 10.1146/annurev.med.53.082901.104018 Boyer-Diaz, 2021, Pan-PPAR agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease, J. Hepatol., 74, 1188, 10.1016/j.jhep.2020.11.045 Devchand, 1996, The PPARalpha-leukotriene B4 pathway to inflammation control, Nature, 384, 39, 10.1038/384039a0 Korbecki, 2019, Self-regulation of the inflammatory response by peroxisome proliferator-activated receptors, Inflamm. Res., 68, 443, 10.1007/s00011-019-01231-1 Brocker, 2017, Hepatocyte-specific PPARA expression exclusively promotes agonist-induced cell proliferation without influence from nonparenchymal cells, Am. J. Physiol. Gastrointest. Liver Physiol., 312, G283, 10.1152/ajpgi.00205.2016 Ip, 2004, Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice, Hepatology, 39, 1286, 10.1002/hep.20170 Pawlak, 2014, The transrepressive activity of peroxisome proliferator-activated receptor alpha is necessary and sufficient to prevent liver fibrosis in mice, Hepatology, 60, 1593, 10.1002/hep.27297 Rodriguez-Vilarrupla, 2012, PPARalpha activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats, J. Hepatol., 56, 1033, 10.1016/j.jhep.2011.12.008 Chen, 2015, Oleoylethanolamide, an endogenous PPAR-alpha ligand, attenuates liver fibrosis targeting hepatic stellate cells, Oncotarget, 6, 42530, 10.18632/oncotarget.6466 Hiukka, 2010, PPARalpha: an emerging therapeutic target in diabetic microvascular damage, Nat. Rev. Endocrinol., 6, 454, 10.1038/nrendo.2010.89 Lefebvre, 2006, Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis, J. Clin. Invest., 116, 571, 10.1172/JCI27989 Han, 2005, Beneficial vascular and metabolic effects of peroxisome proliferator-activated receptor-alpha activators, Hypertension, 46, 1086, 10.1161/01.HYP.0000187900.36455.4c Roberts, 2000, Apoptosis and proliferation in nongenotoxic carcinogenesis: species differences and role of PPARalpha, Toxicol. Lett., 112-113, 49, 10.1016/S0378-4274(99)00243-X de la Rosa Rodriguez, 2018, The whole transcriptome effects of the PPARalpha agonist fenofibrate on livers of hepatocyte humanized mice, BMC Genomics, 19, 443, 10.1186/s12864-018-4834-3 Rakhshandehroo, 2009, Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human, PLoS One, 4, 10.1371/journal.pone.0006796 Wanders, 2006, Biochemistry of mammalian peroxisomes revisited, Annu. Rev. Biochem., 75, 295, 10.1146/annurev.biochem.74.082803.133329 Francque, 2021, Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors, Nat. Rev. Gastroenterol. Hepatol., 18, 24, 10.1038/s41575-020-00366-5 Sung, 2004, Tumor necrosis factor-alpha inhibits peroxisome proliferator-activated receptor gamma activity at a posttranslational level in hepatic stellate cells, Am. J. Physiol. Gastrointest. Liver Physiol., 286, G722, 10.1152/ajpgi.00411.2003 Eng, 2000, New insights into hepatic stellate cell activation: the simple becomes complex, Am. J. Physiol. Gastrointest. Liver Physiol., 279, G7, 10.1152/ajpgi.2000.279.1.G7 Miyahara, 2000, Peroxisome proliferator-activated receptors and hepatic stellate cell activation, J. Biol. Chem., 275, 35715, 10.1074/jbc.M006577200 Hazra, 2004, Peroxisome proliferator-activated receptor gamma induces a phenotypic switch from activated to quiescent hepatic stellate cells, J. Biol. Chem., 279, 11392, 10.1074/jbc.M310284200 Ghosh, 2004, Disruption of transforming growth factor beta signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator-activated receptor gamma, Arthritis Rheum., 50, 1305, 10.1002/art.20104 Marra, 2000, Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells, Gastroenterology, 119, 466, 10.1053/gast.2000.9365 Galli, 2002, Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro, Gastroenterology, 122, 1924, 10.1053/gast.2002.33666 Zhao, 2006, PPARgamma agonists prevent TGFbeta1/Smad3-signaling in human hepatic stellate cells, Biochem. Biophys. Res. Commun., 350, 385, 10.1016/j.bbrc.2006.09.069 Kawaguchi, 2004, Pioglitazone prevents hepatic steatosis, fibrosis, and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet, Biochem. Biophys. Res. Commun., 315, 187, 10.1016/j.bbrc.2004.01.038 Tomita, 2004, Pioglitazone prevents alcohol-induced fatty liver in rats through up-regulation of c-Met, Gastroenterology, 126, 873, 10.1053/j.gastro.2003.12.008 Galli, 2000, Peroxisome proliferator-activated receptor gamma transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells, Hepatology, 31, 101, 10.1002/hep.510310117 Ghosh, 2003, PPARgamma ligand attenuates PDGF-induced mesangial cell proliferation: role of MAP kinase, Kidney Int., 64, 52, 10.1046/j.1523-1755.2003.00054.x Ricote, 1998, The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation, Nature, 391, 79, 10.1038/34178 Moran-Salvador, 2013, Cell-specific PPARgamma deficiency establishes anti-inflammatory and anti-fibrogenic properties for this nuclear receptor in non-parenchymal liver cells, J. Hepatol., 59, 1045, 10.1016/j.jhep.2013.06.023 Leclercq, 2006, Limited therapeutic efficacy of pioglitazone on progression of hepatic fibrosis in rats, Gut, 55, 1020, 10.1136/gut.2005.079194 Jain MR GS, Bhoi B, Rathod R, Trivedi C, Rath AC, Sharma A, Patel U, Patel H, Ranvir R, Saroglitazar attenuates primary sclerosing cholangitis in MDR−/− mice model: a comparison with obeticholic acid. Hepatology 2020;72m Number 1 (Suppl) - 1270. Siddiqui M IM, Parmar DV, Borg B, Douglas D, Loo NM, Lazas D, Younes ZH, Vellanki R, Bainbridge JD, Sanyal AJ. Saroglitazar, adual PPARα/γ agonist, resolved steatohepatitis in a randomized double blind placebo controlled phase 2 proof of concept pilot trial. HEPATOLOGY 2020;72, Number 1 (Suppl) - 1695. Hellemans, 2003, PPARbeta regulates vitamin A metabolism-related gene expression in hepatic stellate cells undergoing activation, J. Lipid Res., 44, 280, 10.1194/jlr.M200376-JLR200 Chen, 2018, Insights into the role of PPARbeta/delta in NAFLD, Int. J. Mol. Sci., 19 Barak, 2002, Effects of peroxisome proliferator-activated receptor delta on placentation, adiposity, and colorectal cancer, Proc. Natl. Acad. Sci. U. S. A., 99, 303, 10.1073/pnas.012610299 Odegaard, 2011, Alternative macrophage activation and metabolism, Annu. Rev. Pathol., 6, 275, 10.1146/annurev-pathol-011110-130138 Akiyama, 2004, Peroxisome proliferator-activated receptor beta/delta regulates very low density lipoprotein production and catabolism in mice on a Western diet, J. Biol. Chem., 279, 20874, 10.1074/jbc.M312802200 Shan, 2008, Ligand activation of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) attenuates carbon tetrachloride hepatotoxicity by downregulating proinflammatory gene expression, Toxicol. Sci., 105, 418, 10.1093/toxsci/kfn142 Iwaisako, 2012, Protection from liver fibrosis by a peroxisome proliferator-activated receptor delta agonist, Proc. Natl. Acad. Sci. U. S. A., 109, E1369, 10.1073/pnas.1202464109 Hellemans, 2003, Peroxisome proliferator-activated receptor-beta signaling contributes to enhanced proliferation of hepatic stellate cells, Gastroenterology, 124, 184, 10.1053/gast.2003.50015 Kostadinova, 2012, GW501516-activated PPARbeta/delta promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation, Cell Biosci., 2, 34, 10.1186/2045-3701-2-34 Staels, 2013, Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, Hepatology, 58, 1941, 10.1002/hep.26461 Fougerat, 2020, Peroxisome proliferator-activated receptors and their novel ligands as candidates for the treatment of non-alcoholic fatty liver disease, Cells, 9 Souza-Mello, 2015, Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease, World J. Hepatol., 7, 1012, 10.4254/wjh.v7.i8.1012 Schattenberg, 2021, A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA, J. Hepatol., 74, 1344, 10.1016/j.jhep.2021.01.013 Francque SM BP, Ratziu V, Anstee QM, Bugianesi E, Sanyal AJ, Loomba R, Harrison SA, Balabanska IR, Mateva L, Lanthier N, Alkhouri N, Moreno C, Schattenberg JM, Stefanova-Petrova D, Vonghia L, Rouzier R, Guillaume M, Leroy V, Romero-Gomez M, Hodge AD, Huot-Marchand P, Sabin N, Baudin M, Abitbol J, Broqua P, Junien J, Abdelmalek MF. The panPPAR agonist Lanifibranor induces both resolution of NASH and regression of fibrosis after 24 weeks of treatment in non-cirrhotic NASH: results of the native phase 2b trial. HEPATOLOGY 2020;72, Number 1 (Suppl) - Abstract 12. Corpechot, 2018, A placebo-controlled trial of bezafibrate in primary biliary cholangitis, N. Engl. J. Med., 378, 2171, 10.1056/NEJMoa1714519 Zhang, 2012, A role for protein inhibitor of activated STAT1 (PIAS1) in lipogenic regulation through SUMOylation-independent suppression of liver X receptors, J. Biol. Chem., 287, 37973, 10.1074/jbc.M112.403139 Lopez-Velazquez JA, Carrillo-Cordova LD, Chavez-Tapia NC, et al. Nuclear receptors in nonalcoholic fatty liver disease. J. Lipids 2012;2012:139875. Beaven, 2011, Liver X receptor signaling is a determinant of stellate cell activation and susceptibility to fibrotic liver disease, Gastroenterology, 140, 1052, 10.1053/j.gastro.2010.11.053 Mallat, 2011, The liver X receptor in hepatic stellate cells: a novel antifibrogenic target?, J. Hepatol., 55, 1452, 10.1016/j.jhep.2011.05.018 Wang, 2006, Activation of the liver X receptor protects against hepatic injury in endotoxemia by suppressing Kupffer cell activation, Shock, 25, 141, 10.1097/01.shk.0000191377.78144.d9 Zhu, 2010, Macrophage ABCA1 reduces MyD88-dependent Toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol, J. Lipid Res., 51, 3196, 10.1194/jlr.M006486 Ito, 2015, LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling, Elife, 4, 10.7554/eLife.08009 Zelcer, 2006, Liver X receptors as integrators of metabolic and inflammatory signaling, J. Clin. Invest., 116, 607, 10.1172/JCI27883 Beltowski, 2008, Liver X receptors (LXR) as therapeutic targets in dyslipidemia, Cardiovasc. Ther., 26, 297, 10.1111/j.1755-5922.2008.00062.x Xing, 2016, Liver X receptor alpha is essential for the capillarization of liver sinusoidal endothelial cells in liver injury, Sci. Rep., 6, 21309, 10.1038/srep21309 Lafoz, 2020, The endothelium as a driver of liver fibrosis and regeneration, Cells, 9 Huang P, Kaluba B, Jiang XL, et al. Liver X receptor inverse agonist SR9243 suppresses nonalcoholic Steatohepatitis intrahepatic inflammation and fibrosis. Biomed. Res. Int. 2018;2018:8071093. Griffett K, Welch RD, Flaveny CA, et al. The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis. Mol Metab 2015;4:353–7. Wagner, 2011, Nuclear receptors in liver disease, Hepatology, 53, 1023, 10.1002/hep.24148 Vogel, 2000, An immortalized rat liver stellate cell line (HSC-T6): a new cell model for the study of retinoid metabolism in vitro, J. Lipid Res., 41, 882, 10.1016/S0022-2275(20)32030-7 Ulven, 1998, Expression of retinoic acid receptor and retinoid X receptor subtypes in rat liver cells: implications for retinoid signalling in parenchymal, endothelial, Kupffer and stellate cells, Eur. J. Cell Biol., 77, 111, 10.1016/S0171-9335(98)80078-2 Tsuji, 2015, Docking simulations suggest that all-trans retinoic acid could bind to retinoid X receptors, J. Comput. Aided Mol. Des., 29, 975, 10.1007/s10822-015-9869-9 Zhou, 2012, The controversial role of retinoic acid in fibrotic diseases: analysis of involved signaling pathways, Int. J. Mol. Sci., 14, 226, 10.3390/ijms14010226 Okuno, 1997, Retinoids exacerbate rat liver fibrosis by inducing the activation of latent TGF-beta in liver stellate cells, Hepatology, 26, 913 Okuno, 2002, Retinoids in liver fibrosis and cancer, Front. Biosci., 7, d204, 10.2741/okuno Ye, 2010, All-trans retinoic acid diminishes collagen production in a hepatic stellate cell line via suppression of active protein-1 and c-Jun N-terminal kinase signal, J. Huazhong Univ. Sci. Technolog. Med. Sci., 30, 726, 10.1007/s11596-010-0648-5 Hellemans, 2004, Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoids, Hepatology, 39, 97, 10.1002/hep.20015 Cortes, 2019, Retinoic acid receptor-beta is downregulated in hepatocellular carcinoma and cirrhosis and its expression inhibits myosin-driven activation and durotaxis in hepatic stellate cells, Hepatology, 69, 785, 10.1002/hep.30193 Wang, 2008, Effect of all-trans retinoic acid on liver fibrosis induced by common bile duct ligation in rats, J. Huazhong Univ. Sci. Technolog. Med. Sci., 28, 553, 10.1007/s11596-008-0514-x He, 2011, Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct-ligated rats and human hepatic cells, Hepatology, 53, 548, 10.1002/hep.24047 Cai, 2014, All-trans-retinoic acid improves cholestasis in alpha-naphthylisothiocyanate-treated rats and Mdr2−/− mice, J. Pharmacol. Exp. Ther., 349, 94, 10.1124/jpet.113.209353 Mukhopadhyay, 2010, Transcriptional regulation of cannabinoid receptor-1 expression in the liver by retinoic acid acting via retinoic acid receptor-gamma, J. Biol. Chem., 285, 19002, 10.1074/jbc.M109.068460 Wang, 2007, Effects of retinoic acid on the development of liver fibrosis produced by carbon tetrachloride in mice, Biochim. Biophys. Acta, 1772, 66, 10.1016/j.bbadis.2006.08.009 Hisamori, 2008, All-trans-retinoic acid ameliorates carbon tetrachloride-induced liver fibrosis in mice through modulating cytokine production, Liver Int., 28, 1217, 10.1111/j.1478-3231.2008.01745.x Yang, 2008, Antagonizing TGF-beta induced liver fibrosis by a retinoic acid derivative through regulation of ROS and calcium influx, Biochem. Biophys. Res. Commun., 365, 484, 10.1016/j.bbrc.2007.10.203 Okuno, 1999, Increased 9,13-di-cis-retinoic acid in rat hepatic fibrosis: implication for a potential link between retinoid loss and TGF-beta mediated fibrogenesis in vivo, J. Hepatol., 30, 1073, 10.1016/S0168-8278(99)80262-1 le Maire A, Teyssier C, Balaguer P, et al. Regulation of RXR-RAR heterodimers by RXR- and RAR-specific ligands and their combinations. Cells 2019;8. Saponaro, 2020, Selective thyroid hormone receptor-beta (TRbeta) agonists: new perspectives for the treatment of metabolic and neurodegenerative disorders, Front. Med. (Lausanne), 7, 331, 10.3389/fmed.2020.00331 Abdel-Moneim, 2020, Relationship of thyroid dysfunction with cardiovascular diseases: updated review on heart failure progression, Hormones (Athens), 19, 301, 10.1007/s42000-020-00208-8 Pagadala, 2012, Prevalence of hypothyroidism in nonalcoholic fatty liver disease, Dig. Dis. Sci., 57, 528, 10.1007/s10620-011-2006-2 Bano, 2016, Thyroid function and the risk of nonalcoholic fatty liver disease: the Rotterdam study, J. Clin. Endocrinol. Metab., 101, 3204, 10.1210/jc.2016-1300 Manka, 2017, Thyroid hormone receptor regulates hepatic stellate cell activation, J. Hepatol., 66, S582, 10.1016/S0168-8278(17)31587-8 Marek, 2005, Pregnenolone-16alpha-carbonitrile inhibits rodent liver fibrogenesis via PXR (pregnane X receptor)-dependent and PXR-independent mechanisms, Biochem. J., 387, 601, 10.1042/BJ20041598 Marek, 2009, Low affinity glucocorticoid binding site ligands as potential anti-fibrogenics, Comp. Hepatol., 8, 1, 10.1186/1476-5926-8-1 Weiner, 1987, The effects of dexamethasone on in vitro collagen gene expression, J. Biol. Chem., 262, 6955, 10.1016/S0021-9258(18)48184-7 Bolkenius, 2004, Glucocorticoids decrease the bioavailability of TGF-beta which leads to a reduced TGF-beta signaling in hepatic stellate cells, Biochem. Biophys. Res. Commun., 325, 1264, 10.1016/j.bbrc.2004.10.164 Kim, 2016, Glucocorticoids have opposing effects on liver fibrosis in hepatic stellate and immune cells, Mol. Endocrinol., 30, 905, 10.1210/me.2016-1029 Koorneef, 2018, Selective glucocorticoid receptor modulation prevents and reverses nonalcoholic fatty liver disease in male mice, Endocrinology, 159, 3925 Comeglio, 2021, Treatment potential of LPCN 1144 on liver health and metabolic regulation in a non-genomic, high fat diet induced NASH rabbit model, J. Endocrinol. Invest., 10.1007/s40618-021-01522-7 Shimizu, 2003, Impact of oestrogens on the progression of liver disease, Liver Int., 23, 63, 10.1034/j.1600-0676.2003.00811.x Xu, 2002, Estrogen reduces CCL4- induced liver fibrosis in rats, World J. Gastroenterol., 8, 883, 10.3748/wjg.v8.i5.883 Yasuda, 1999, Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rats, Hepatology, 29, 719, 10.1002/hep.510290307 Poynard, 2001, Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis c, J. Hepatol., 34, 730, 10.1016/S0168-8278(00)00097-0 Codes, 2007, Liver fibrosis in women with chronic hepatitis C: evidence for the negative role of the menopause and steatosis and the potential benefit of hormone replacement therapy, Gut, 56, 390, 10.1136/gut.2006.101931 Codes, 2007, Chronic hepatitis C and fibrosis: evidences for possible estrogen benefits, Braz. J. Infect. Dis., 11, 371, 10.1590/S1413-86702007000300014 Massard, 2006, Natural history and predictors of disease severity in chronic hepatitis C, J. Hepatol., 44, S19, 10.1016/j.jhep.2005.11.009 Han, 2010, A novel bile acid-activated vitamin D receptor signaling in human hepatocytes, Mol. Endocrinol., 24, 1151, 10.1210/me.2009-0482 Gascon-Barre, 2003, The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells, Hepatology, 37, 1034, 10.1053/jhep.2003.50176 Pawlak, 2015, Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease, J. Hepatol., 62, 720, 10.1016/j.jhep.2014.10.039 Burri L, Thoresen GH, Berge RK. The role of PPARalpha activation in liver and muscle. PPAR Res. 2010;2010. Wang, 2020, PPARs as metabolic regulators in the liver: lessons from liver-specific PPAR-null mice, Int. J. Mol. Sci., 21 Zhang, 2013, Peroxisome proliferator-activated receptor-gamma as a therapeutic target for hepatic fibrosis: from bench to bedside, Cell. Mol. Life Sci., 70, 259, 10.1007/s00018-012-1046-x Zhang, 2016, Hepatic peroxisome proliferator-activated receptor gamma signaling contributes to alcohol-induced hepatic Steatosis and inflammation in mice, Alcohol. Clin. Exp. Res., 40, 988, 10.1111/acer.13049 Liu, 2018, The role of PPAR-delta in metabolism, inflammation, and cancer: many characters of a critical transcription factor, Int. J. Mol. Sci., 19 Zingarelli, 2010, Peroxisome proliferator-activated receptor {delta} regulates inflammation via NF-{kappa}B signaling in polymicrobial sepsis, Am. J. Pathol., 177, 1834, 10.2353/ajpath.2010.091010 Tong, 2019, PPARdelta attenuates hepatic steatosis through autophagy-mediated fatty acid oxidation, Cell Death Dis., 10, 197, 10.1038/s41419-019-1458-8 Ahn, 2014, Expression of liver X receptor correlates with intrahepatic inflammation and fibrosis in patients with nonalcoholic fatty liver disease, Dig. Dis. Sci., 59, 2975, 10.1007/s10620-014-3289-x Thomas DG, Doran AC, Fotakis P, et al. LXR suppresses inflammatory gene expression and neutrophil migration through cis-repression and cholesterol efflux. Cell Rep. 2018;25:3774–3785 e4. Larrede, 2009, 29, 1930 McFadden, 2010, Activation of liver X receptor (LXR) enhances de novo fatty acid synthesis in bovine mammary epithelial cells, J. Dairy Sci., 93, 4651, 10.3168/jds.2010-3202 Dong, 2015, Activation of the liver X receptor by agonist TO901317 improves hepatic insulin resistance via suppressing reactive oxygen species and JNK pathway, PLoS One, 10 Harrison, 2021, Effects of resmetirom on noninvasive endpoints in a 36-week phase 2 active treatment extension study in patients with NASH, Hepatol. Commun., 5, 573, 10.1002/hep4.1657 Harrison, 2019, Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, Lancet, 394, 2012, 10.1016/S0140-6736(19)32517-6 Loomba R, 2020, VK2809, a novel liver-directed thyroid receptor agonist, produces durable reductions in liver fat in patients with non-alcoholic fatty liver disease: results of 4-week follow-up assessment from a 12-week phase 2 randomized, placebo-controlled trial, J. Hepatol., 73, S19 Day, 1989, Endocrinology, 125, 459, 10.1210/endo-125-1-459 Berkenstam, 2008, The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans, Proc. Natl. Acad. Sci. U. S. A., 105, 663, 10.1073/pnas.0705286104 Gullberg, 2002, Requirement for thyroid hormone receptor beta in T3 regulation of cholesterol metabolism in mice, Mol. Endocrinol., 16, 1767, 10.1210/me.2002-0009