Targeting nuclear receptors for NASH/MASH: From bench to bedside^☆

Abstract

The onset of metabolic dysfunction-associated steatohepatitis (MASH) or non-alcoholic steatohepatitis (NASH) represents a tipping point leading to liver injury and subsequent hepatic complications in the natural progression of what is now termed metabolic dysfunction-associated steatotic liver diseases (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). With no pharmacological treatment currently available for MASH/NASH, the race is on to develop drugs targeting multiple facets of hepatic metabolism, inflammation, and pro-fibrotic events, which are major drivers of MASH. Nuclear receptors (NRs) regulate genomic transcription upon binding to lipophilic ligands and govern multiple aspects of liver metabolism and inflammation. Ligands of NRs may include hormones, lipids, bile acids, and synthetic ligands, which upon binding to NRs regulate the transcriptional activities of target genes. NR ligands are presently the most promising drug candidates expected to receive approval from the United States Food and Drug Administration as a pharmacological treatment for MASH. This review aims to cover the current understanding of NRs, including nuclear hormone receptors, non-steroid hormone receptors, circadian NRs, and orphan NRs, which are currently undergoing clinical trials for MASH treatment, along with NRs that have shown promising results in preclinical studies.

Keywords

Nuclear receptor (NR) / Metabolic dysfunction-associated steatohepatitis (MASH) / Metabolic dysfunction-associated steatotic liver disease (MASLD) / Transcription factor / Liver / Drug

Author's contribution

Rohit A. Sinha: Conceptualization, Data curation, Formal anal-ysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing e original draft, Writing e review & editing.

Declaration of competing interest

The author declares that there is no conflicts of interest.

Acknowledgements

This study was supported by the SERB (CRG/2022/002149) and Wellcome Trust/DBT India Alliance Fellowship [IA/I/16/2/502691].

References

[1] Younossi Z, Tacke F, Arrese M, et al. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology. 2019;69: 2672-2682. https://doi.org/10.1002/hep.30251.

[2] Wong VW, Ekstedt M, Wong GL, Hagström H. Changing epidemiology, global trends and implications for outcomes of NAFLD. J Hepatol. 2023;79:842-852. https://doi.org/10.1016/j.jhep.2023.04.036.

[3] Chandrakumaran A, Siddiqui MS. Implications of nonalcoholic steatohepatitis as the cause of end-stage liver disease before and after liver transplant. Gastroenterol Clin N Am. 2020;49:165-178. https://doi.org/10.1016/j.gtc.2019.09.005.

[4] Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017;66:1138-1153. https://doi.org/10.1136/gutjnl-2017-313884.

[5] Burra P, Becchetti C, Germani G. NAFLD and liver transplantation: disease burden, current management and future challenges. JHEP Rep. 2020;2: 100192. https://doi.org/10.1016/j.jhepr.2020.100192.

[6] Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic steatohepatitis: a review. JAMA. 2020;323:1175-1183. https://doi.org/10.1001/jama.2020.2298.

[7] Wallace SJ, Tacke F, Schwabe RF, Henderson NC. Understanding the cellular interactome of non-alcoholic fatty liver disease. JHEP Rep. 2022;4:100524. https://doi.org/10.1016/j.jhepr.2022.100524.

[8] Tewari A, Rajak S, Raza S, et al. Targeting extracellular RNA mitigates hepatic lipotoxicity and liver injury in NASH. Cells. 2023;12:1845. https://doi.org/10.3390/cells12141845.

[9] Xiao Y, Kim M, Lazar MA. Nuclear receptors and transcriptional regulation in non-alcoholic fatty liver disease. Mol Metab. 2021;50:101119. https://doi.org/10.1016/j.molmet.2020.101119.

[10] Evans RM, Mangelsdorf DJ. Nuclear receptors, RXR, and the big bang. Cell. 2014;157:255-266. https://doi.org/10.1016/j.cell.2014.03.012.

[11] Arnal JF, Fontaine C, Adlanmerini M, Lenfant F. Special issue on non-genomic ac-tions of nuclear receptors: an evolutionary and physiological perspective. Mol Cell Endocrinol. 2023;564:111884. https://doi.org/10.1016/j.mce.2023.111884.

[12] Sinha RA, Singh BK, Yen PM. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol. 2018;14:259-269. https://doi.org/10.1038/nrendo.2018.10.

[13] Sinha R, Yen PM. Cellular Action of Thyroid Hormone. In: Feingold KR, Anawalt B, Blackman MR, et al.eds. com, South Dartmouth (MA): MDText. Inc; 2018.

[14] Puymirat J, Gadbois P, Dussault L, Garceau L, Dussault JH. Production of a specific polyclonal antibody against the rat beta thyroid receptor, using synthetic peptide as antigen. Acta Endocrinol (Copenh). 1991;125:397-400. https://doi.org/10.1530/acta.0.1250397.

[15] Fava G, Ueno Y, Glaser S, et al. Thyroid hormone inhibits biliary growth in bile duct-ligated rats by PLC/IP(3) /Ca(2þ)-dependent downregulation of SRC/ERK1/2. Am J Physiol Cell Physiol. 2007;292:C1467eC1475. https://doi.org/10.1152/ajpcell.00575.2006.

[16] Tapia G, Santibáñez C, Farías J, et al. Kupffer-cell activity is essential for thy-roid hormone rat liver preconditioning. Mol Cell Endocrinol. 2010;323: 292-297. https://doi.org/10.1016/j.mce.2010.03.014.

[17] Manka P, Coombes J, Bechmann L, et al. Thyroid hormone receptor regulates hepatic stellate cell activation. J Hepatol. 2017;66:S582. https://doi.org/10.1016/S0168-8278(17)31587-8.

[18] Sheikhi V, Heidari Z. Association of subclinical hypothyroidism with nonal-coholic fatty liver disease in patients with type 2 diabetes mellitus: a cross-sectional study. Adv Biomed Res. 2022;11:124. https://doi.org/10.4103/abr.abr_15_21.

[19] Kim D, Vazquez-Montesino LM, Escober JA, et al. Low thyroid function in nonalcoholic fatty liver disease is an independent predictor of all-cause and cardiovascular mortality. Am J Gastroenterol. 2020;115:1496-1504. https://doi.org/10.14309/ajg.0000000000000654.

[20] Kim D, Kim W, Joo SK, Bae JM, Kim JH, Ahmed A. Subclinical hypothyroidism and low-normal thyroid function are associated with nonalcoholic steatohe-patitis and fibrosis. Clin Gastroenterol Hepatol. 2018;16:123-131.e1. https://doi.org/10.1016/j.cgh.2017.08.014.

[21] Pagadala MR, Zein CO, Dasarathy S, Yerian LM, Lopez R, McCullough AJ. Prevalence of hypothyroidism in nonalcoholic fatty liver disease. Dig Dis Sci. 2012;57:528-534. https://doi.org/10.1007/s10620-011-2006-2.

[22] Gardner CJ, Richardson P, Wong C, Polavarapu N, Kemp GJ, Cuthbertson DJ. Hypothyroidism in a patient with non-alcoholic fatty liver disease. BMJ. 2011;342:c7199. https://doi.org/10.1136/bmj.c7199.

[23] Kalaitzakis E. Fatigue in non-alcoholic fatty liver disease: is there a role for hypothyroidism. Gut. 2009;58:149-150.

[24] Bohinc BN, Michelotti G, Xie G, et al. Repair-related activation of hedgehog signaling in stromal cells promotes intrahepatic hypothyroidism. Endocri-nology. 2014;155:4591-4601. https://doi.org/10.1210/en.2014-1302.

[25] Cable EE, Finn PD, Stebbins JW, et al. Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist. Hepatology. 2009;49:407-417. https://doi.org/10.1002/hep.22572.

[26] Perra A, Simbula G, Simbula M, et al. Thyroid hormone (T3) and TRbeta agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats. FASEB J. 2008;22: 2981-2989. https://doi.org/10.1096/fj.08-108464.

[27] Zhou J, Tripathi M, Ho JP, et al. Thyroid hormone decreases hepatic steatosis, inflammation, and fibrosis in a dietary mouse model of nonalcoholic steato-hepatitis. Thyroid. 2022;32:725-738. https://doi.org/10.1089/thy.2021.0621.

[28] Iannucci LF, Cioffi F, Senese R, et al. Metabolomic analysis shows differential hepatic effects of T2 and T 3 in rats after short-term feeding with high fat diet. Sci Rep. 2017;7:2023. https://doi.org/10.1038/s41598-017-02205-1.

[29] Zhou J, Sinha RA, Yen PM. The roles of autophagy and thyroid hormone in the pathogenesis and treatment of NAFLD. Hepatoma Res. 2021;7:72. https://doi.org/10.20517/2394-5079.2021.82.

[30] Sinha RA, Singh BK, Yen PM. Reciprocal crosstalk between autophagic and endocrine signaling in metabolic homeostasis. Endocr Rev. 2017;38:69-102. https://doi.org/10.1210/er.2016-1103.

[31] Sinha RA, Yen PM. Thyroid hormone-mediated autophagy and mitochondrial turnover in NAFLD. Cell Biosci. 2016;6:46. https://doi.org/10.1186/s13578-016-0113-7.

[32] Sinha RA, You SH, Zhou J, et al. Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy. J Clin Invest. 2012;122:2428-2438. https://doi.org/10.1172/JCI60580.

[33] Araki O, Ying H, Zhu XG, Willingham MC, Cheng SY. Distinct dysregulation of lipid metabolism by unliganded thyroid hormone receptor isoforms. Mol Endocrinol. 2009;23:308-315. https://doi.org/10.1210/me.2008-0311.

[34] Chaves C, Bruinstroop E, Refetoff S, Yen PM, Anselmo J. Increased hepatic fat content in patients with resistance to thyroid hormone beta. Thyroid. 2021;31:1127-1134. https://doi.org/10.1089/thy.2020.0651.

[35] Bruinstroop E, Dalan R, Cao Y, et al. Low-dose levothyroxine reduces intra-hepatic lipid content in patients with type 2 diabetes mellitus and NAFLD. J Clin Endocrinol Metab. 2018;103:2698-2706. https://doi.org/10.1210/jc.2018-00475.

[36] Li L, Song Y, Shi Y, Sun L. Thyroid hormone receptor-b agonists in NAFLD therapy: possibilities and challenges. J Clin Endocrinol Metab. 2023;108: 1602-1613. https://doi.org/10.1210/clinem/dgad072.

[37] Harrison SA, Bashir MR, Guy CD, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019;394:2012-2024. https://doi.org/10.1016/S0140-673632517-6.

[38] Harrison SA, Bashir M, Moussa SE, et al. Effects of resmetirom on noninvasive endpoints in a 36-week phase 2 active treatment extension study in patients with NASH. Hepatol Commun. 2021;5:573-588. https://doi.org/10.1002/hep4.1657.

[39] Younossi ZM, Stepanova M, Taub RA, Barbone JM, Harrison SA. Hepatic fat reduction due to resmetirom in patients with nonalcoholic steatohepatitis is Associated with improvement of quality of life. Clin Gastroenterol Hepatol. 2022;20:1354-1361.e7. https://doi.org/10.1016/j.cgh.2021.07.039.

[40] Javanbakht M, Fishman J, Moloney E, Rydqvist P, Ansaripour A. Early cost-effectiveness and price threshold analyses of resmetirom: an investigational treatment for management of nonalcoholic steatohepatitis. Pharmacoecon Open. 2023;7:93-110. https://doi.org/10.1007/s41669-022-00370-2.

[41] Harrison SA, Bedossa P, Guy CD, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390:497-509. https://doi.org/10.1056/NEJMoa2309000.

[42] Frank F, Ortlund EA, Liu X. Structural insights into glucocorticoid receptor function. Biochem Soc Trans. 2021;49:2333-2343. https://doi.org/10.1042/BST20210419.

[43] Goldstein I, Baek S, Presman DM, Paakinaho V, Swinstead EE, Hager GL. Transcription factor assisted loading and enhancer dynamics dictate the he-patic fasting response. Genome Res. 2017;27:427-439. https://doi.org/10.1101/gr.212175.116.

[44] Lemke U, Krones-Herzig A, Berriel Diaz M, et al. The glucocorticoid receptor controls hepatic dyslipidemia through Hes1. Cell Metab. 2008;8:212-223. https://doi.org/10.1016/j.cmet.2008.08.001.

[45] Robert O, Boujedidi H, Bigorgne A, et al. Decreased expression of the gluco-corticoid receptor-GILZ pathway in Kupffer cells promotes liver inflammation in obese mice. J Hepatol. 2016;64:916-924. https://doi.org/10.1016/j.jhep.2015.11.023.

[46] Rahimi L, Rajpal A, Ismail-Beigi F. Glucocorticoid-induced fatty liver disease. Diabetes Metab Syndr Obes. 2020;13:1133-1145. https://doi.org/10.2147/DMSO.S247379.

[47] Osborne CK, Schiff R. Estrogen-receptor biology: continuing progress and therapeutic implications. J Clin Oncol. 2005;23:1616-1622. https://doi.org/10.1200/JCO.2005.10.036.

[48] Palmisano BT, Zhu L, Stafford JM. Role of estrogens in the regulation of liver lipid metabolism. Adv Exp Med Biol. 2017;1043:227-256. https://doi.org/10.1007/978-3-319-70178-3_12.

[49] Gao H, Bryzgalova G, Hedman E, et al. Long-term administration of estradiol decreases expression of hepatic lipogenic genes and improves insulin sensi-tivity in ob/ob mice: a possible mechanism is through direct regulation of signal transducer and activator of transcription 3. Mol Endocrinol. 2006;20: 1287-1299. https://doi.org/10.1210/me.2006-0012.

[50] Gao H, Fält S, Sandelin A, Gustafsson JA, Dahlman-Wright K. Genome-wide identification of estrogen receptor alpha-binding sites in mouse liver. Mol Endocrinol. 2008;22:10-22. https://doi.org/10.1210/me.2007-0121.

[51] Chow JD, Jones ME, Prelle K, Simpson ER, Boon WC. A selective estrogen re-ceptor a agonist ameliorates hepatic steatosis in the male aromatase knockout mouse. J Endocrinol. 2011;210:323-334. https://doi.org/10.1530/JOE-10-0462.

[52] Guillaume M, Riant E, Fabre A, et al. Selective liver estrogen receptor a modulation prevents steatosis, diabetes, and obesity through the anorectic growth differentiation factor 15 hepatokine in mice. Hepatol Commun. 2019;3:908-924. https://doi.org/10.1002/hep4.1363.

[53] Hart-Unger S, Arao Y, Hamilton KJ, et al. Hormone signaling and fatty liver in females: analysis of estrogen receptor a mutant mice. Int J Obes. 2017;41: 945-954. https://doi.org/10.1038/ijo.2017.50.

[54] Winn NC, Jurrissen TJ, Grunewald ZI, et al. Estrogen receptor-a signaling maintains immunometabolic function in males and is obligatory for exercise-induced amelioration of nonalcoholic fatty liver. Am J Physiol Endocrinol Metab. 2019;316:E156eE167. https://doi.org/10.1152/ajpendo.00259.2018.

[55] Villa A, Della Torre S, Stell A, Cook J, Brown M, Maggi A. Tetradian oscillation of estrogen receptor a is necessary to prevent liver lipid deposition. Proc Natl Acad Sci U S A. 2012;109:11806-11811. https://doi.org/10.1073/pnas.1205797109.

[56] Shu Z, Zhang G, Zhu X, Xiong W. Estrogen receptor a mediated M1/M2 macrophages polarization plays a critical role in NASH of female mice. Bio-chem Biophys Res Commun. 2022;596:63-70. https://doi.org/10.1016/j.bbrc.2022.01.085.

[57] DiStefano JK. NAFLD and NASH in Postmenopausal women: implications for diagnosis and treatment. Endocrinology. 2020;161:bqaa134. https://doi.org/10.1210/endocr/bqaa134.

[58] Ryu S, Suh BS, Chang Y, et al. Menopausal stages and non-alcoholic fatty liver disease in middle-aged women. Eur J Obstet Gynecol Reprod Biol. 2015;190: 65-70. https://doi.org/10.1016/j.ejogrb.2015.04.017.

[59] Völzke H, Schwarz S, Baumeister SE, et al. Menopausal status and hepatic steatosis in a general female population. Gut. 2007;56:594-595. https://doi.org/10.1136/gut.2006.115345.

[60] Lonardo A, Nascimbeni F, Ballestri S, et al. Sex differences in nonalcoholic fatty liver disease: state of the art and identification of research gaps. Hepatology. 2019;70:1457-1469. https://doi.org/10.1002/hep.30626.

[61] McKenzie J, Fisher BM, Jaap AJ, Stanley A, Paterson K, Sattar N. Effects of HRT on liver enzyme levels in women with type 2 diabetes: a randomized placebo-controlled trial. Clin Endocrinol (Oxf). 2006;65:40-44. https://doi.org/10.1111/j.1365-2265.2006.02543.x.

[62] Meda C, Barone M, Mitro N, et al. Hepatic ERa accounts for sex differences in the ability to cope with an excess of dietary lipids. Mol Metab. 2020;32: 97-108. https://doi.org/10.1016/j.molmet.2019.12.009.

[63] Erkan G, Yilmaz G, Konca Degertekin C, Akyol G, Ozenirler S. Presence and extent of estrogen receptor-alpha expression in patients with simple steatosis and NASH. Pathol Res Pract. 2013;209:429-432. https://doi.org/10.1016/j.prp.2013.04.010.

[64] Ponnusamy S, Tran QT, Thiyagarajan T, Miller DD, Bridges D, Narayanan R. An estrogen receptor b-selective agonist inhibits non-alcoholic steatohepatitis in preclinical models by regulating bile acid and xenobiotic receptors. Exp Biol Med (Maywood). 2017;242:606-616. https://doi.org/10.1177/1535370216688569.

[65] Rochel N. Vitamin D and its receptor from a structural perspective. Nutrients. 2022;14:2847. https://doi.org/10.3390/nu14142847.

[66] Bouillon R, Marcocci C, Carmeliet G, et al. Skeletal and extraskeletal actions of vitamin D: current evidence and outstanding questions. Endocr Rev. 2019;40: 1109-1151. https://doi.org/10.1210/er.2018-00126.

[67] Yin Y, Yu Z, Xia M, Luo X, Lu X, Ling W. Vitamin D attenuates high fat diet-induced hepatic steatosis in rats by modulating lipid metabolism. Eur J Clin Invest. 2012;42:1189-1196. https://doi.org/10.1111/j.1365-2362.2012.02706.x.

[68] Nakano T, Cheng YF, Lai CY, et al. Impact of artificial sunlight therapy on the progress of non-alcoholic fatty liver disease in rats. J Hepatol. 2011;55: 415-425. https://doi.org/10.1016/j.jhep.2010.11.028.

[69] Raza S, Tewari A, Rajak S, Sinha RA. Vitamins and non-alcoholic fatty liver disease: a molecular insight. Liver Res. 2021;5:62-71. https://doi.org/10.1016/j.livres.2021.03.004.

[70] Bozic M, Guzmán C, Benet M, et al. Hepatocyte vitamin D receptor regulates lipid metabolism and mediates experimental diet-induced steatosis. J Hepatol. 2016;65:748-757. https://doi.org/10.1016/j.jhep.2016.05.031.

[71] García-Monzón C, Petrov PD, Rey E, et al. Angiopoietin-like protein 8 is a novel vitamin D receptor target gene involved in nonalcoholic fatty liver patho-genesis. Am J Pathol. 2018;188:2800-2810. https://doi.org/10.1016/j.ajpath.2018.07.028.

[72] Barchetta I, Cimini FA, Chiappetta C, et al. Relationship between hepatic and systemic angiopoietin-like 3, hepatic vitamin D receptor expression and NAFLD in obesity. Liver Int. 2020;40:2139-2147. https://doi.org/10.1111/liv.14554.

[73] Ding N, Yu RT, Subramaniam N, et al. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell. 2013;153:601-613. https://doi.org/10.1016/j.cell.2013.03.028.

[74] Zhang H, Shen Z, Lin Y, et al. Vitamin D receptor targets hepatocyte nuclear factor 4a and mediates protective effects of vitamin D in nonalcoholic fatty liver disease. J Biol Chem. 2020;295:3891-3905. https://doi.org/10.1074/jbc.RA119.011487.

[75] Tao T, Kobelski MM, Saini V, Demay MB. Adipose-specific VDR deletion leads to hepatic steatosis in female mice fed a low-fat diet. Endocrinology. 2022;163:bqab249. https://doi.org/10.1210/endocr/bqab249.

[76] Jahn D, Dorbath D, Schilling AK, et al. Intestinal vitamin D receptor modulates lipid metabolism, adipose tissue inflammation and liver steatosis in obese mice. Biochim Biophys Acta, Mol Basis Dis. 2019;1865:1567-1578. https://doi.org/10.1016/j.bbadis.2019.03.007.

[77] Gascon-Barré M, Demers C, Mirshahi A, Néron S, Zalzal S, Nanci A. The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells. Hepatology. 2003;37:1034-1042. https://doi.org/10.1053/jhep.2003.50176.

[78] Dong B, Zhou Y, Wang W, et al. Vitamin D receptor activation in liver mac-rophages ameliorates hepatic inflammation, steatosis, and insulin resistance in mice. Hepatology. 2020;71:1559-1574. https://doi.org/10.1002/hep.30937.

[79] Tourkochristou E, Mouzaki A, Triantos C. Gene polymorphisms and biological effects of vitamin D receptor on nonalcoholic fatty liver disease development and progression. Int J Mol Sci. 2023;24:8288. https://doi.org/10.3390/ijms24098288.

[80] Jaroenlapnopparat A, Suppakitjanusant P, Ponvilawan B, Charoenngam N. Vitamin D-related genetic variations and nonalcoholic fatty liver disease: a systematic review. Int J Mol Sci. 2022;23:9122. https://doi.org/10.3390/ijms23169122.

[81] Gibson PS, Quaglia A, Dhawan A, et al. Vitamin D status and associated genetic polymorphisms in a cohort of UK children with non-alcoholic fatty liver disease. Pediatr Obes. 2018;13:433-441. https://doi.org/10.1111/ijpo.12293.

[82] Arai T, Atsukawa M, Tsubota A, et al. Association of vitamin D levels and vitamin D-related gene polymorphisms with liver fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease. Dig Liver Dis. 2019;51: 1036-1042. https://doi.org/10.1016/j.dld.2018.12.022.

[83] Petkovich M, Chambon P. Retinoic acid receptors at 35 years. J Mol Endocrinol. 2022;69:T13eT24. https://doi.org/10.1530/JME-22-0097.

[84] He Y, Gong L, Fang Y, et al. The role of retinoic acid in hepatic lipid homeo-stasis defined by genomic binding and transcriptome profiling. BMC Genomics. 2013;14:575. https://doi.org/10.1186/1471-2164-14-575.

[85] Yang F, He Y, Liu HX, et al. All-trans retinoic acid regulates hepatic bile acid homeostasis. Biochem Pharmacol. 2014;91:483-489. https://doi.org/10.1016/j.bcp.2014.08.018.

[86] Kim SC, Kim CK, Axe D, et al. All-trans-retinoic acid ameliorates hepatic steatosis in mice by a novel transcriptional cascade. Hepatology. 2014;59: 1750-1760. https://doi.org/10.1002/hep.26699.

[87] Tsuchiya H, Ikeda Y, Ebata Y, et al. Retinoids ameliorate insulin resistance in a leptin-dependent manner in mice. Hepatology. 2012;56:1319-1330. https://doi.org/10.1002/hep.25798.

[88] Trasino SE, Tang XH, Jessurun J, Gudas LJ. Retinoic acid receptor b2 agonists restore glycaemic control in diabetes and reduce steatosis. Diabetes Obes Metab. 2016;18:142-151. https://doi.org/10.1111/dom.12590.

[89] Tang XH, Melis M, Lu C, et al. A retinoic acid receptor b 2 agonist attenuates transcriptome and metabolome changes underlying nonalcohol-associated fatty liver disease. J Biol Chem. 2021;297:101331. https://doi.org/10.1016/j.jbc.2021.101331.

[90] Trasino SE, Tang XH, Jessurun J, Gudas LJ. A retinoic acid receptor b2 agonist reduces hepatic stellate cell activation in nonalcoholic fatty liver disease. J Mol Med (Berl). 2016;94:1143-1151. https://doi.org/10.1007/s00109-016-1434-z.

[91] Liu Y, Chen H, Wang J, Zhou W, Sun R, Xia M. Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease. Am J Clin Nutr. 2015;102:130-137. https://doi.org/10.3945/ajcn.114.105155.

[92] Saeed A, Dullaart RPF, Schreuder TCMA, Blokzijl H, Faber KN. Disturbed vitamin a metabolism in non-alcoholic fatty liver disease (NAFLD). Nutrients. 2017;10:29. https://doi.org/10.3390/nu10010029.

[93] Ren G, Kim T, Kim HS, et al. A small molecule, UAB126, reverses diet-induced obesity and its associated metabolic disorders. Diabetes. 2020;69:2003-2016. https://doi.org/10.2337/db19-1001.

[94] Puengel T, Liu H, Guillot A, Heymann F, Tacke F, Peiseler M. Nuclear receptors linking metabolism, inflammation, and fibrosis in nonalcoholic fatty liver disease. Int J Mol Sci. 2022;23:2668. https://doi.org/10.3390/ijms23052668.

[95] Königshofer P, Brusilovskaya K, Petrenko O, et al. Nuclear receptors in liver fibrosis. Biochim Biophys Acta, Mol Basis Dis. 2021;1867:166235. https://doi.org/10.1016/j.bbadis.2021.166235.

[96] Cariello M, Piccinin E, Moschetta A. Transcriptional regulation of metabolic pathways via lipid-sensing nuclear receptors PPARs, FXR, and LXR in NASH. Cell Mol Gastroenterol Hepatol. 2021;11:1519-1539. https://doi.org/10.1016/j.jcmgh.2021.01.012.

[97] Wahli W, Michalik L. PPARs at the crossroads of lipid signaling and inflam-mation. Trends Endocrinol Metab. 2012;23:351-363. https://doi.org/10.1016/j.tem.2012.05.001.

[98] Staels B, Butruille L, Francque S. Treating NASH by targeting peroxisome proliferator-activated receptors. J Hepatol. 2023;79:1302-1316. https://doi.org/10.1016/j.jhep.2023.07.004.

[99] Sinha RA, Rajak S, Singh BK, Yen PM. Hepatic lipid catabolism via PPARa-lysosomal crosstalk. Int J Mol Sci. 2020;21:2391. https://doi.org/10.3390/ijms21072391.

[100] Frohnert BI, Hui TY, Bernlohr DA. Identification of a functional peroxisome proliferator-responsive element in the murine fatty acid transport protein gene. J Biol Chem. 1999;274:3970-3977. https://doi.org/10.1074/jbc.274.7.3970.

[101] Gulick T, Cresci S, Caira T, Moore DD, Kelly DP. The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc Natl Acad Sci U S A. 1994;91:11012-11016. https://doi.org/10.1073/pnas.91.23.11012.

[102] Lundåsen T, Hunt MC, Nilsson LM, et al. PPARalpha is a key regulator of he-patic FGF21. Biochem Biophys Res Commun. 2007;360:437-440. https://doi.org/10.1016/j.bbrc.2007.06.068.

[103] Montagner A, Polizzi A, Fouché E, et al. Liver PPARa is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut. 2016;65: 1202-1214. https://doi.org/10.1136/gutjnl-2015-310798.

[104] Fernández-Alvarez A, Alvarez MS, Gonzalez R, Cucarella C, MuntanéJ, Casado M. Human SREBP1c expression in liver is directly regulated by peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem. 2011;286:21466-21477. https://doi.org/10.1074/jbc.M110.209973.

[105] Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Perox-isome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest. 1999;103:1489-1498. https://doi.org/10.1172/JCI6223.

[106] Mansouri RM, Baugé E, Staels B, Gervois P. Systemic and distal repercussions of liver-specific peroxisome proliferator-activated receptor-alpha control of the acute-phase response. Endocrinology. 2008;149:3215-3223. https://doi.org/10.1210/en.2007-1339.

[107] Ip E, Farrell G, Hall P, Robertson G, Leclercq I. Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepa-titis in mice. Hepatology. 2004;39:1286-1296. https://doi.org/10.1002/hep.20170.

[108] Pawlak M, Baugé E, Bourguet W, et al. The transrepressive activity of perox-isome proliferator-activated receptor alpha is necessary and sufficient to prevent liver fibrosis in mice. Hepatology. 2014;60:1593-1606. https://doi.org/10.1002/hep.27297.

[109] Gervois P, Vu-Dac N, Kleemann R, et al. Negative regulation of human fibrin-ogen gene expression by peroxisome proliferator-activated receptor alpha agonists via inhibition of CCAAT box/enhancer-binding protein beta. J Biol Chem. 2001;276:33471-33477. https://doi.org/10.1074/jbc.M102839200.

[110] Francque S, Verrijken A, Caron S, et al. PPARa gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J Hepatol. 2015;63:164-173. https://doi.org/10.1016/j.jhep.2015.02.019.

[111] Nakajima A, Eguchi Y, Yoneda M, et al. Randomised clinical trial: pemafibrate, a novel selective peroxisome proliferator-activated receptor a modulator (SPPARMa), versus placebo in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2021;54:1263-1277. https://doi.org/10.1111/apt.16596.

[112] Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-a and -d, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150:1147-1159.e5. https://doi.org/10.1053/j.gastro.2016.01.038.

[113] Loomba R, Sanyal AJ, Kowdley KV, et al. Randomized, controlled trial of the FGF 21 analogue pegozafermin in NASH. N Engl J Med. 2023;389:998-1008. https://doi.org/10.1056/NEJMoa2304286.

[114] Flowers MT, Ntambi JM. Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism. Curr Opin Lipidol. 2008;19:248-256. https://doi.org/10.1097/MOL.0b013e3282f9b54d.

[115] Liu S, Hatano B, Zhao M, et al. Role of peroxisome proliferator-activated re-ceptor {delta}/{beta} in hepatic metabolic regulation. J Biol Chem. 2011;286: 1237-1247. https://doi.org/10.1074/jbc.M110.138115.

[116] Zarei M, Barroso E, Palomer X, et al. Hepatic regulation of VLDL receptor by PPARb/d and FGF 21 modulates non-alcoholic fatty liver disease. Mol Metab. 2018;8:117-131. https://doi.org/10.1016/j.molmet.2017.12.008.

[117] Inoue M, Ohtake T, Motomura W, et al. Increased expression of PPARgamma in high fat diet-induced liver steatosis in mice. Biochem Biophys Res Commun. 2005;336:215-222. https://doi.org/10.1016/j.bbrc.2005.08.070.

[118] Morán-Salvador E, López-Parra M, García-Alonso V, et al. Role for PPARg in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts. FASEB J. 2011;25:2538-2550. https://doi.org/10.1096/fj.10-173716.

[119] Matsusue K, Haluzik M, Lambert G, et al. Liver-specific disruption of PPAR-gamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest. 2003;111:737-747. https://doi.org/10.1172/JCI17223.

[120] Nan YM, Fu N, Wu WJ, et al. Rosiglitazone prevents nutritional fibrosis and steatohepatitis in mice. Scand J Gastroenterol. 2009;44:358-365. https://doi.org/10.1080/00365520802530861.

[121] Hazra S, Miyahara T, Rippe RA, Tsukamoto H. PPAR gamma and hepatic stellate cells. Comp Hepatol. 2004;Suppl 1:S7. https://doi.org/10.1186/1476-5926-2-S1-S7.

[122] Ni XX, Ji PX, Chen YX, et al. Regulation of the macrophage-hepatic stellate cell interaction by targeting macrophage peroxisome proliferator-activated re-ceptor gamma to prevent non-alcoholic steatohepatitis progression in mice. Liver Int. 2022;42:2696-2712. https://doi.org/10.1111/liv.15441.

[123] Ni XX, Li XY, Wang Q, Hua J. Regulation of peroxisome proliferator-activated receptor-gamma activity affects the hepatic stellate cell activation and the progression of NASH via TGF-b1/Smad signaling pathway. J Physiol Biochem. 2021;77:35-45. https://doi.org/10.1007/s13105-020-00777-7.

[124] Panebianco C, Oben JA, Vinciguerra M, Pazienza V. Senescence in hepatic stellate cells as a mechanism of liver fibrosis reversal: a putative synergy between retinoic acid and PPAR-gamma signalings. Clin Exp Med. 2017;17: 269-280. https://doi.org/10.1007/s10238-016-0438-x.

[125] Luo W, Xu Q, Wang Q, Wu H, Hua J. Effect of modulation of PPAR-g activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease. Sci Rep. 2017;7:44612. https://doi.org/10.1038/srep44612.

[126] Morán-Salvador E, Titos E, Rius B, et al. Cell-specific PPARg deficiency es-tablishes anti-inflammatory and anti-fibrogenic properties for this nuclear receptor in non-parenchymal liver cells. J Hepatol. 2013;59:1045-1053. https://doi.org/10.1016/j.jhep.2013.06.023.

[127] Wu HM, Ni XX, Xu QY, Wang Q, Li XY, Hua J. Regulation of lipid-induced macrophage polarization through modulating peroxisome proliferator-activated receptor-gamma activity affects hepatic lipid metabolism via a Toll-like receptor 4/NF-kB signaling pathway. J Gastroenterol Hepatol. 2020;35:1998-2008. https://doi.org/10.1111/jgh.15025.

[128] Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature. 2007;447:1116-1120. https://doi.org/10.1038/nature05894.

[129] Pettinelli P, Videla LA. Up-regulation of PPAR-gamma mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction. J Clin Endocrinol Metab. 2011;96:1424-1430. https://doi.org/10.1210/jc.2010-2129.

[130] Harrison SA, Alkhouri N, Davison BA, et al. Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase IIb study. J Hepatol. 2020;72:613-626. https://doi.org/10.1016/j.jhep.2019.10.023.

[131] Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176-1184. https://doi.org/10.1053/j.gastro.2008.06.047.

[132] Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steato-hepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) trial. Gastroenterology. 2008;135:100-110. https://doi.org/10.1053/j.gastro.2008.03.078.

[133] Gawrieh S, Noureddin M, Loo N, et al. Saroglitazar, a PPAR-a/g agonist, for treatment of NAFLD: a randomized controlled double-blind phase 2 trial. Hepatology. 2021;74:1809-1824. https://doi.org/10.1002/hep.31843.

[134] Francque SM, Bedossa P, Ratziu V, et al. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N Engl J Med. 2021;385:1547-1558. https://doi.org/10.1056/NEJMoa2036205.

[135] Panzitt K, Wagner M. FXR in liver physiology: multiple faces to regulate liver metabolism. Biochim Biophys Acta Mol Basis Dis. 2021;1867:166133. https://doi.org/10.1016/j.bbadis.2021.166133.

[136] Chiang JY. Bile acid metabolism and bile acid receptor signaling in metabolic diseases and therapy. Liver Res. 2021;5:103-104. https://doi.org/10.1016/j.livres.2021.08.002.

[137] Ma Y, Huang Y, Yan L, Gao M, Liu D. Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm Res. 2013;30: 1447-1457. https://doi.org/10.1007/s11095-013-0986-7.

[138] Gai Z, Visentin M, Gui T, et al. Effects of farnesoid X receptor activation on arachidonic acid metabolism, NF-kB signaling, and hepatic inflammation. Mol Pharmacol. 2018;94:802-811. https://doi.org/10.1124/mol.117.111047.

[139] Zhang S, Wang J, Liu Q, Harnish DC. Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol. 2009;51:380-388. https://doi.org/10.1016/j.jhep.2009.03.025.

[140] Clifford BL, Sedgeman LR, Williams KJ, et al. FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption. Cell Metab. 2021;33:1671-1684.e4. https://doi.org/10.1016/j.cmet.2021.06.012.

[141] Watanabe M, Houten SM, Wang L, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. 2004;113: 1408-1418. https://doi.org/10.1172/JCI21025.

[142] Pineda Torra I, Claudel T, Duval C, Kosykh V, Fruchart JC, Staels B. Bile acids induce the expression of the human peroxisome proliferator-activated re-ceptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol. 2003;17:259-272. https://doi.org/10.1210/me.2002-0120.

[143] Xu W, Cui C, Cui C, et al. Hepatocellular cystathionine g lyase/hydrogen sul-fide attenuates nonalcoholic fatty liver disease by activating farnesoid X re-ceptor. Hepatology. 2022;76:1794-1810. https://doi.org/10.1002/hep.32577.

[144] Fickert P, Fuchsbichler A, Moustafa T, et al. 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. https://doi.org/10.2353/ajpath.2009.090114.

[145] Schumacher JD, Guo GL. Pharmacologic modulation of bile acid-FXR-FGF15/FGF19 pathway for the treatment of nonalcoholic steatohepatitis. Handb Exp Pharmacol. 2019;256:325-357. https://doi.org/10.1007/164_2019_228.

[146] Tian S, Chen M, Wang B, Han Y, Shang H, Chen J. Salvianolic acid B blocks hepatic stellate cell activation via FGF19/FGFR4 signaling. Ann Hepatol. 2021;20:100259. https://doi.org/10.1016/j.aohep.2020.07.013.

[147] Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear re-ceptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956-965. https://doi.org/10.1016/S0140-673661933-4.

[148] Sanyal AJ, Ratziu V, Loomba R, et al. Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis. J Hepatol. 2023;79: 1110-1120. https://doi.org/10.1016/j.jhep.2023.07.014.

[149] Sanyal AJ, Lopez P, Lawitz EJ, et al. Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial. Nat Med. 2023;29:392-400. https://doi.org/10.1038/s41591-022-02200-8.

[150] Sherwin X, Singh BK, Yen PM, Sinha RA. Activation of liver X receptors (LXRs) increases sphingolipid biosynthesis in hepatic cells. Matters Select. 2016;2: 1-5. https://doi.org/10.19185/MATTERS.201611000022.

[151] Endo-Umeda K, Makishima M. Liver X receptors regulate cholesterol meta-bolism and immunity in hepatic nonparenchymal cells. Int J Mol Sci. 2019;20: 5045. https://doi.org/10.3390/ijms20205045.

[152] Liu Y, Qiu DK, Ma X. Liver X receptors bridge hepatic lipid metabolism and inflammation. J Dig Dis. 2012;13:69-74. https://doi.org/10.1111/j.1751-2980.2011.00554.x.

[153] Sinha RA, Singh BK, Zhou J, et al. Loss of ULK 1 increases RPS6KB1-NCOR1 repression of NR1H/LXR-mediated Scd1 transcription and augments lip-otoxicity in hepatic cells. Autophagy. 2017;13:169-186. https://doi.org/10.1080/15548627.2016.1235123.

[154] Venteclef N, Jakobsson T, Ehrlund A, et al. GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH-1 and LXRbeta in the hepatic acute phase response. Genes Dev. 2010;24:381-395. https://doi.org/10.1101/gad.545110.

[155] Ito A, Hong C, Rong X, et al. LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling. Elife. 2015;4:e08009. https://doi.org/10.7554/eLife.08009.

[156] Endo-Umeda K, Nakashima H, Umeda N, Seki S, Makishima M. Dysregulation of Kupffer cells/macrophages and natural killer T cells in steatohepatitis in LXRa knockout male mice. Endocrinology. 2018;159:1419-1432. https://doi.org/10.1210/en.2017-03141.

[157] Beaven SW, Wroblewski K, Wang J, et al. Liver X receptor signaling is a determinant of stellate cell activation and susceptibility to fibrotic liver dis-ease. Gastroenterology. 2011;140:1052-1062. https://doi.org/10.1053/j.gastro.2010.11.053.

[158] Kim H, Park C, Kim TH. Targeting liver X receptors for the treatment of non-alcoholic fatty liver disease. Cells. 2023;12:1292. https://doi.org/10.3390/cells12091292.

[159] Kliewer SA, Moore JT, Wade L, et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell. 1998;92:73-82. https://doi.org/10.1016/s0092-8674(00)80900-9.

[160] Roth A, Looser R, Kaufmann M, Meyer UA. Sterol regulatory element binding protein 1 interacts with pregnane X receptor and constitutive androstane receptor and represses their target genes. Pharmacogenetics Genom. 2008;18: 325-337. https://doi.org/10.1097/FPC.0b013e3282f706-0.

[161] Zhou J, Febbraio M, Wada T, et al. Hepatic fatty acid transporter Cd 36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology. 2008;134:556-567. https://doi.org/10.1053/j.gastro.2007.11.037.

[162] Zhao LY, Xu JY, Shi Z, Englert NA, Zhang SY. Pregnane X receptor (PXR) deficiency improves high fat diet-induced obesity via induction of fibroblast growth factor 15 (FGF15) expression. Biochem Pharmacol. 2017;142:194-203. https://doi.org/10.1016/j.bcp.2017.07.019.

[163] Bitter A, Rümmele P, Klein K, et al. Pregnane X receptor activation and silencing promote steatosis of human hepatic cells by distinct lipogenic mechanisms. Arch Toxicol. 2015;89:2089-2103. https://doi.org/10.1007/s00204-014-1348-x.

[164] Sayaf K, Zanotto I, Russo FP, Gabbia D,De Martin S. The nuclear receptor PXR in chronic liver disease. Cells. 2021;11:61. https://doi.org/10.3390/cells11010061.

[165] Feng D, Liu T, Sun Z, et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science. 2011;331: 1315-1319. https://doi.org/10.1126/science.1198125.

[166] Zhang Y, Fang B, Emmett MJ, et al. GENE REGULATION. Discrete functions of nuclear receptor Rev-erba couple metabolism to the clock. Science. 2015;348: 1488-1492. https://doi.org/10.1126/science.aab3021.

[167] Solt LA, Wang Y, Banerjee S, et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature. 2012;485:62-68. https://doi.org/10.1038/nature11030.

[168] Griffett K, Hayes ME, Boeckman MP, Burris TP. The role of REV-ERB in NASH. Acta Pharmacol Sin. 2022;43:1133-1140. https://doi.org/10.1038/s41401-022-00883-w.

[169] Griffett K, Bedia-Diaz G, Elgendy B, Burris TP. REV-ERB agonism improves liver pathology in a mouse model of NASH. PLoS One. 2020;15:e0236000. https://doi.org/10.1371/journal.pone.0236000.

[170] Duez H, Staels B. The nuclear receptors Rev-erbs and RORs integrate circadian rhythms and metabolism. Diab Vasc Dis Res. 2008;5:82-88. https://doi.org/10.3132/dvdr.2008.0014.

[171] Solt LA, Burris TP. Action of RORs and their ligands in (patho) physiology. Trends Endocrinol Metab. 2012;23:619-627. https://doi.org/10.1016/j.tem.2012.05.012.

[172] Kang HS, Okamoto K, Takeda Y, et al. Transcriptional profiling reveals a role for RORalpha in regulating gene expression in obesity-associated inflamma-tion and hepatic steatosis. Physiol Genom. 2011;43:818-828. https://doi.org/10.1152/physiolgenomics.00206.2010.

[173] Lau P, Fitzsimmons RL, Raichur S, Wang SC, Lechtken A, Muscat GE. The orphan nuclear receptor, RORalpha, regulates gene expression that controls lipid metabolism: staggerer (SG/SG) mice are resistant to diet-induced obesity. J Biol Chem. 2008;283:18411-18421. https://doi.org/10.1074/jbc.M710526200.

[174] Zhang Y, Papazyan R, Damle M, et al. The hepatic circadian clock fine-tunes the lipogenic response to feeding through RORa/g. Genes Dev. 2017;31: 1202-1211. https://doi.org/10.1101/gad.302323.117.

[175] Kim K, Boo K, Yu YS, et al. RORa controls hepatic lipid homeostasis via negative regulation of PPARg transcriptional network. Nat Commun. 2017;8: 162. https://doi.org/10.1038/s41467-017-00215-1.

[176] Han YH, Kim HJ, Na H, et al. RORa Induces KLF4-mediated M2 polarization in the liver macrophages that protect against nonalcoholic steatohepatitis. Cell Rep. 2017;20:124-135. https://doi.org/10.1016/j.celrep.2017.06.017.

[177] He B, Nohara K, Park N, et al. The small molecule nobiletin targets the molecular Oscillator to enhance circadian rhythms and protect against metabolic syn-drome. Cell Metab. 2016;23:610-621. https://doi.org/10.1016/j.cmet.2016.03.007.

[178] Kumar N, Kojetin DJ, Solt LA, et al. Identification of SR3335 (ML-176): a synthetic RORa selective inverse agonist. ACS Chem Biol. 2011;6:218-222. https://doi.org/10.1021/cb1002762.

[179] Xia H, Dufour CR, Giguère V. ERRa as a Bridge between transcription and function: role in liver metabolism and disease. Front Endocrinol(Lausanne). 2019;10:206. https://doi.org/10.3389/fendo.2019.00206.

[180] Singh BK, Sinha RA, Tripathi M, et al. Thyroid hormone receptor and ERRa coordinately regulate mitochondrial fission, mitophagy, biogenesis, and func-tion. Sci Signal. 2018;11:eaam5855. https://doi.org/10.1126/scisignal.aam5855.

[181] Luo J, Sladek R, Carrier J, Bader JA, Richard D, Giguère V. Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha. Mol Cell Biol. 2003;23:7947-7956. https://doi.org/10.1128/MCB.23.22.7947-7956.2003.

[182] Chaveroux C, Eichner LJ, Dufour CR, et al. Molecular and genetic crosstalks between mTOR and ERRa are key determinants of rapamycin-induced nonalcoholic fatty liver. Cell Metab. 2013;17:586-598. https://doi.org/10.1016/j.cmet.2013.03.003.

[183] B’chir W, Dufour CR, Ouellet C, et al. Divergent role of estrogen-related re-ceptor a in lipid- and fasting-induced hepatic steatosis in mice. Endocrinology. 2018;159:2153-2164. https://doi.org/10.1210/en.2018-00115.

[184] Yang M, Liu Q, Huang T, et al. Dysfunction of estrogen-related receptor alpha-dependent hepatic VLDL secretion contributes to sex disparity in NAFLD/NASH development. Theranostics. 2020;10:10874-10891. https://doi.org/10.7150/thno.47037.

[185] Chen CY, Li Y, Zeng N, et al. Inhibition of estrogen-related receptor a blocks liver steatosis and steatohepatitis and attenuates triglyceride biosynthesis. Am J Pathol. 2021;191:1240-1254. https://doi.org/10.1016/j.ajpath.2021.04.007.

[186] Tian J, Marino R, Johnson C, Locker J. Binding of drug-activated CAR/Nr1i3 alters metabolic regulation in the liver. iScience. 2018;9:209-228. https://doi.org/10.1016/j.isci.2018.10.018.

[187] Wahlang B, Prough RA, Falkner KC, et al. Polychlorinated biphenyl-xenobiotic nuclear receptor interactions regulate energy metabolism, behavior, and inflammation in non-alcoholic-steatohepatitis. Toxicol Sci. 2016;149: 396-410. https://doi.org/10.1093/toxsci/kfv250.

[188] Marmugi A, Lukowicz C, Lasserre F, et al. Activation of the constitutive androstane receptor induces hepatic lipogenesis and regulates Pnpla 3 gene expression in a LXR-independent way. Toxicol Appl Pharmacol. 2016;303: 90-100. https://doi.org/10.1016/j.taap.2016.05.006.

[189] Dauwe Y, Mary L, Oliviero F, et al. Steatosis and metabolic disorders associ-ated with synergistic activation of the CAR/RXR heterodimer by pesticides. Cells. 2023;12:1201. https://doi.org/10.3390/cells12081201.

[190] Takizawa D, Kakizaki S, Horiguchi N, Yamazaki Y, Tojima H, Mori M. Consti-tutive active/androstane receptor promotes hepatocarcinogenesis in a mouse model of non-alcoholic steatohepatitis. Carcinogenesis. 2011;32:576-583. https://doi.org/10.1093/carcin/bgq277.

[191] Yamazaki Y, Kakizaki S, Horiguchi N, et al. The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic stea-tohepatitis. Gut. 2007;56:565-574. https://doi.org/10.1136/gut.2006.093260.

[192] Dong B, Saha PK, Huang W, et al. Activation of nuclear receptor CAR ame-liorates diabetes and fatty liver disease. Proc Natl Acad Sci U S A. 2009;106: 18831-18836. https://doi.org/10.1073/pnas.0909731106.

[193] Elbel EE, Lavine JE, Downes M, et al. Hepatic nuclear receptor expression associates with features of histology in pediatric nonalcoholic fatty liver disease. Hepatol Commun. 2018;2:1213-1226. https://doi.org/10.1002/hep4.1232.

[194] Seol W, Choi HS, Moore DD. An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science. 1996;272:1336-1339. https://doi.org/10.1126/science.272.5266.1336.

[195] Boulias K, Katrakili N, Bamberg K, Underhill P, Greenfield A, Talianidis I. Regulation of hepatic metabolic pathways by the orphan nuclear receptor SHP. EMBO J. 2005;24:2624-2633. https://doi.org/10.1038/sj.emboj.7600728.

[196] Benet M, Guzmán C, Pisonero-Vaquero S, et al. Repression of the nuclear receptor small heterodimer partner by steatotic drugs and in advanced nonalcoholic fatty liver disease. Mol Pharmacol. 2015;87:582-594. https://doi.org/10.1124/mol.114.096313.

[197] Kim YC, Qi M, Dong X, et al. Transgenic mice lacking FGF15/19-SHP phos-phorylation display altered bile acids and gut bacteria, promoting nonalco-holic fatty liver disease. J Biol Chem. 2023;299:104946. https://doi.org/10.1016/j.jbc.2023.104946.

[198] Magee N, Zou A, Ghosh P, Ahamed F, Delker D, Zhang Y. Disruption of hepatic small heterodimer partner induces dissociation of steatosis and inflammation in experimental nonalcoholic steatohepatitis. J Biol Chem. 2020;295: 994-1008. https://doi.org/10.1074/jbc.RA119.010233.

[199] Myronovych A, Salazar-Gonzalez RM, Ryan KK, et al. The role of small het-erodimer partner in nonalcoholic fatty liver disease improvement after sleeve gastrectomy in mice. Obesity (Silver Spring). 2014;22:2301-2311. https://doi.org/10.1002/oby.20890.

[200] Zhou LM, Fan JH, Xu MM, et al. Epiberberine regulates lipid synthesis through SHP (NR0B2) to improve non-alcoholic steatohepatitis. Biochim Biophys Acta Mol Basis Dis. 2023;1869:166639. https://doi.org/10.1016/j.bbadis.2023.166639.

[201] Zou A, Magee N, Deng F, Lehn S, Zhong C, Zhang Y. Hepatocyte nuclear re-ceptor SHP suppresses inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis. J Biol Chem. 2018;293:8656-8671. https://doi.org/10.1074/jbc.RA117.001653.

[202] Huang J, Iqbal J, Saha PK, et al. Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver. Hepatology. 2007;46:147-157. https://doi.org/10.1002/hep.21632.

[203] Bechmann LP, Kocabayoglu P, Sowa JP, et al. Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepati-tis. Hepatology. 2013;57:1394-1406. https://doi.org/10.1002/hep.26225.

[204] Huang KW, Reebye V, Czysz K, et al. Liver activation of hepatocellular nuclear factor-4a by small activating RNA rescues dyslipidemia and improves meta-bolic profile. Mol Ther Nucleic Acids. 2020;19:361-370. https://doi.org/10.1016/j.omtn.2019.10.044.

[205] Ren H, Hu F, Wang D, et al. Sirtuin 2 prevents liver steatosis and metabolic disorders by deacetylation of hepatocyte nuclear factor 4a. Hepatology. 2021;74:723-740. https://doi.org/10.1002/hep.31773.

[206] Thymiakou E, Othman A, Hornemann T, Kardassis D. Defects in high density lipoprotein metabolism and hepatic steatosis in mice with liver-specific ablation of hepatocyte nuclear factor 4A. Metabolism. 2020;110:154307. https://doi.org/10.1016/j.metabol.2020.154307.

[207] Xu Y, Hu S, Jadhav K, et al. Hepatocytic activating transcription factor 3 protects against steatohepatitis via hepatocyte nuclear factor 4a. Diabetes. 2021;70:2506-2517. https://doi.org/10.2337/db21-0181.

[208] Xu Y, Zhu Y, Hu S, et al. Hepatocyte nuclear factor 4a prevents the steatosis-to-NASH progression by regulating p53 and bile acid signaling (in mice). Hepatology. 2021;73:2251-2265. https://doi.org/10.1002/hep.31604.

[209] Yu D, Chen G, Pan M, et al. High fat diet-induced oxidative stress blocks he-patocyte nuclear factor 4a and leads to hepatic steatosis in mice. J Cell Physiol. 2018;233:4770-4782. https://doi.org/10.1002/jcp.26270.

[210] Kiselyuk A, Lee SH, Farber-Katz S, et al. HNF4a antagonists discovered by a high-throughput screen for modulators of the human insulin promoter. Chem Biol. 2012;19:806-818. https://doi.org/10.1016/j.chembiol.2012.05.014.

[211] Gunewardena S, Huck I, Walesky C, Robarts D, Weinman S, Apte U. Progressive loss of hepatocyte nuclear factor 4 alpha activity in chronic liver diseases in humans. Hepatology. 2022;76:372-386. https://doi.org/10.1002/hep.32326.

[212] Sun Y, Demagny H, Schoonjans K. Emerging functions of the nuclear receptor LRH-1 in liver physiology and pathology. Biochim Biophys Acta Mol Basis Dis. 2021;1867:166145. https://doi.org/10.1016/j.bbadis.2021.166145.

[213] Miranda DA, Krause WC, Cazenave-Gassiot A, et al. LRH-1 regulates hepatic lipid homeostasis and maintains arachidonoyl phospholipid pools critical for phospholipid diversity. JCI Insight. 2018;3:e96151. https://doi.org/10.1172/jci.insight.96151.