Research progress on the mechanism of action and drugs of FXR in the treatment of cholestatic liver diseases

doi:10.19803/j.1672-8629.20240531

Abstract

Abstract: Objective To review the mechanism of action of farnesoid X receptor (FXR) in the treatment of cholestatic liver disease and the research progress of drugs targeting FXR. Methods The mechanism of FXR in improving cholestasis by regulating bile acid production, metabolism, transport and enterohepatic circulation was expounded. The anti-inflammatory, antioxidant and anti-fibrosis effects and mechanisms of FXR were discussed. The therapeutic effects of steroid and non-steroid FXR agonists and FXR antagonists and the progress of clinical trials were reviewed. Results and Conclusion Cholestatic liver disease is a group of common clinical diseases with cholestasis as the main manifestation. Its pathogenic mechanism is complex, which also determines the complexity of medication to a certain extent. Nuclear receptors can regulate the homeostasis of bile acid and are currently a hot research topic for drug targets for the treatment of cholestasis. FXR plays a vital role in maintaining bile acid balance. It is a physiological bile acid nuclear receptor and is regarded as the main therapeutic target for cholestasis and related diseases. With the continuous deepening of research on FXR, it was found that it plays a core regulatory role in regulating bile acid homeostasis, anti-inflammation, anti-oxidation and anti-fibrosis aspects. FXR agonists and FXR antagonists are constantly being developed to treat cholestatic liver diseases.

Key words: cholestatic liver disease, farnesoid X receptor, farnesoid X receptor agonist, farnesoid X receptor antagonist

CLC Number:

R975.5

HU Li, YANG Weifeng, LIU Ting, FENG Weihong, LU Chenna, LI Chun. Research progress on the mechanism of action and drugs of FXR in the treatment of cholestatic liver diseases[J]. Chinese Journal of Pharmacovigilance, 2024, 21(10): 1184-1191.

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https://zgywjj.magtechjournal.com/EN/Y2024/V21/I10/1184

References

[1] Expert Committee on the 2015 update of expert consensus on the diagnosis and treatment of cholestatic liver disease. Expert consensus on the diagnosis and treatment of cholestatic liver disease:2015 update the 2015 update of expert consensus on the diagnosis and treatment of cholestatic liver disease. Expert consensus on the diagnosis and treatment of cholestatic liver disease:2015 update[J]. Chinese Journal of Liver Diseases (Electronic Version)(中国肝脏病杂志电子版), 2015, 7(2): 1-11.
[2] WANG AJ, WANG YY, LIANG X, et al.Advances in mechanism and drug studies of PPAR-based treatment of cholestatic liver disease[J]. Chinese Journal of Clinical Pharmacology and Therapeutics(中国临床药理学与治疗学), 2023, 28(7): 796-808.
[3] SHAH RA, KOWDLEY KV.Current and potential treatments for primary biliary cholangitis[J]. The Lancet. Gastroenterology & Hepatology, 2019, 5(3): 306-315.
[4] YOU H, DUAN WJ, LI SX, et al.Guidelines on the diagnosis and management of primary biliary cholangitis(2021)[J]. Journal of Clinical Hepatology(临床肝胆病杂志), 2022, 38(1): 35-41.
[5] YAO ZW, CHEN L, HU M, et al.The discovery of a new potent FXR agonist based on natural product screening[J]. Bioorganic Chemistry, 2023, 143(12): 106979.
[6] YANG XL, TIAN SC, PANG B, et al.Advanced progression in the mechanism of bile acid metabolism targeting FXR[J]. Hans Journal of Biomedicine(生物医学), 2018, 8(4): 62-68.
[7] COLLINS SL, STINE JG, BISANZ JE, et al.Bile acids and the gut microbiota: metabolic interactions and impacts on disease[J]. Nature Reviews. Microbiology, 2022, 21(4): 236-247.
[8] ZHU SS, LU X.Characterization of serum bile acid profile in intrahepatic cholestasis and progress in its study[J]. Chinese Hepatology(肝脏), 2022, 27(6): 715-719.
[9] ZENG ZH, LIU RR, TANG L, et al.Interaction between gut microbiota and bile acid metabolism[J]. Chinese Journal of Microecology(中国微生态学杂志), 2021, 33(7): 849-856.
[10] GAO XG, LIU KX, MENG Q.Mechanism of hepatic transporters and metabolic enzymes in cholestatic liver injury[J]. Drug Evaluation Research(药物评价研究), 2017, 40(9): 1210-1215.
[11] GUO ZY, DU LN, ZHANG YJ, et al.Advances in the study of anti-cholestasis of herbs and its active components based on regulation of farnesoid X receptor[J]. Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology(世界科学技术-中医药现代化), 2022, 24(11): 4199-4206.
[12] KIM YC, SEOK SM, ZHANG Y, et al.Intestinal FGF15/19 physiologically repress hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A[J]. Nature Communications, 2020, 11(1): 5969-5982.
[13] LI XK, LU WQ, KHARITONENKOV A, et al.Targeting the FGF19-FGFR4 pathway for cholestatic, metabolic, and cancerous diseases[J]. Journal of Internal Medicine, 2024, 295(3): 292-312.
[14] WAHLSTROM A, SAYIN SI, MARSCHAL HU, et al.Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism[J]. Cell Metabolism, 2016, 24(1): 41-50.
[15] ZHU YY, ZHANG QP, PAN JL, et al.Evolutionary analysis of SLC10 family members and insights into function and expression regulation of lamprey NTCP[J]. Fish Physiology and Biochemistry, 2024, 50(3): 1109-1122.
[16] GEIER A, WAGNER M, DIETRICH CG, et al.Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration[J]. Biochimica et Biophysica Acta, 2006, 1773(3): 283-308.
[17] YANG L, CAO Y, YANG CQ.Mechanisms of cholestasis and related diseases[J]. Journal of Internal Medicine Concepts & Practice(内科理论与实践), 2014, 9(5): 308-312.
[18] ANANTHANARAYANAN M, BALASUBRAMANIAN N, MAKISHIMA M, et al.Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor[J]. The Journal of Biological Chemistry, 2001, 276(31): 28857-28865.
[19] JIANG LY, ZHANG HJ, XIAO DS, et al.Farnesoid X receptor (FXR): structures and ligands[J]. Computational and Structural Biotechnology Journal, 2021, 19(10): 2148-2159.
[20] HAN TQ, ZHU ZG, JIANG ZY, et al.Progress on the bile acid salt output pump of the lateral membrane of hepatocyte bile ducts[J]. International Journal of Digestive Diseases(国际消化病杂志), 2004(5): 259-260.
[21] ALEO MD, SHAH F, HE K, et al.Evaluating the role of multidrug resistance protein 3 (MDR3) inhibition in predicting drug-induced liver injury using 125 pharmaceuticals[J]. Chemical Research in Toxicology, 2017, 30(5): 1219-1229.
[22] DUAN XY, HU JP.Recent advances in drug development targeting bile acids transporters and related disease[J]. Acta Pharmaceutica Sinica(药学学报), 2022, 57(12): 3576-3586.
[23] ZHENG MQ, ZHAI YJ, YU YB, et al.TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response[J]. Cell Metabolism, 2024, 36(24): 1-18.
[24] HALILBASIC E, CLAUDEL T, TRAUNER M.Bile acid transporters and regulatory nuclear receptors in the liver and beyond[J]. Journal of Hepatology, 2012, 58(1): 155-168.
[25] ZHOU HP, HYLEMON PB.Bile acids are nutrient signaling hormones[J]. Steroids, 2014, 86(6): 62-68.
[26] CHEN J, ZHANG SJ.The role of inflammation in cholestatic liver injury[J]. Journal of Inflammation Research, 2023, 16: 4527-4540.
[27] KANG JY, LUO J, GAO ZT, et al.Research progress on the inflammatory mechanisms of cholestatic liver injury[J]. Basic and Clinical Medicine(基础医学与临床), 2022, 42(5): 809-813.
[28] HAO HP, CAO LJ, JIANG CT, et al. Farnesoid X receptor regulation of the NLRP3 inflammasome underlies cholestasis-associated sepsis[J]. Cell Metabolism, 2017, 25(4): 856-867.e5.
[29] TRAUNER M, CHUNG CH, STERLING K, et al.PRIMIS: design of a pivotal, randomized, phase 3 study evaluating the safety and efficacy of the nonsteroidal farnesoid X receptor agonist cilofexor in noncirrhotic patients with primary sclerosing cholangitis[J]. BMC Gastroenterology, 2023, 23(1): 75-85.
[30] RENGA B, MIGLIORATI M, MENCARELLI A, et al.Reciprocal regulation of the bile acid-activated receptor FXR and the interferon-gamma-STAT-1 pathway in macrophages[J]. Biochimica et Biophysica Acta, 2009, 1792(6): 564-573.
[31] LUO M, ZHAO FK, CHENG H, et al.Macrophage polarization: an important role in inflammatory diseases[J]. Frontiers in Immunology, 2024, 15: 1352946.
[32] JAROONWITCHAWAN T, ARIMOCHI H, SASAKI Y, et al.Stimulation of the farnesoid X receptor promotes M2 macrophage polarization[J]. Frontiers in Immunology, 2023, 14: 1065790.
[33] HAN CY, KIM TH, KOO JH, et al.Farnesoid X receptor as a regulator of fuel consumption and mitochondrial function[J]. Archives of Pharmacal Research, 2016, 39(8): 1062-1074.
[34] HE D, CHEN P, LIU F, et al.Progress in etiology and pathogenesis of liver fibrosis[J]. Journal of Kunming Medical University(昆明医科大学学报), 2022, 43(11): 165-171.
[35] ZHOU JY, CUI S, HE QX, et al.SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis[J]. Nature Communications, 2020, 11(1): 240-255.
[36] MOON AN, BRIAND F, BREYNER N, et al.Improvement of NASH and liver fibrosis through modulation of the gut-liver axis by a novel intestinal FXR agonist[J]. Biomedicine & Pharmacotherapy, 2024, 173: 116331.
[37] GEGE C, HAMBRUCH E, HAMBRUCH N, et al.Nonsteroidal FXR ligands: current status and clinical applications[J]. Handbook of Experimental Pharmacology, 2019, 256: 167-205.
[38] GE QC, LU LG.Progress in the study of drug therapy for cholestatic liver disease[J]. Chinese Hepatology(肝脏), 2023, 28(11): 1261-1263.
[39] POREZ G, PRAWITT J, GROSS B, et al.Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease[J]. Journal of Lipid Research, 2012, 53(9): 1723-1737.
[40] NEVENS F, ANDREONE P, MAZZELLA G, et al.A placebo-controlled trial of obeticholic acid in primary biliary cholangitis[J]. The New England Journal of Medicine, 2016, 375(7): 631-643.
[41] National Clinical Medical Research Center for Infectious Diseases. Expert consensus on the diagnosis and treatment of intrahepatic cholestasis (version 2021)[J]. Chinese Journal of Clinical Infectious Diseases(中华临床感染病杂志), 2021, 14(6): 401-412.
[42] TIAN CL.Experimental study on the improvement of cholestatic liver injury by FXR agonist Vonafexor[D]. Shijiazhuang: Hebei Medical University, 2023.
[43] SCHRAMM C, WEDEMEYER H, MASON A, et al.Farnesoid X receptor agonist tropifexor attenuates cholestasis in a randomised trial in patients with primary biliary cholangitis[J]. JHEP Reports, 2022, 4(11): 100544.
[44] TRAUNER M, GULAMHUSEIN A, HAMEED B, et al.The nonsteroidal farnesoid X receptor agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with primary sclerosing cholangitis[J]. Hepatology, 2019, 70(3): 788-801.
[45] SCHWABL P, HAMBRUCH E, BUDAS GR, et al.The non-steroidal FXR agonist cilofexor improves portal hypertension and reduces hepatic fibrosis in a rat NASH model[J]. Biomedicines, 2021, 9(1): 60-70.
[46] PANZITT K, ZOLLNER G, MARSCHALL HU, et al.Recent advances on FXR-targeting therapeutics[J]. Molecular and Cellular Endocrinology, 2022, 552: 111678.
[47] MING WH, LUAN ZL, ZHANG XY, et al.Research progress on natural agonists of Farnesoid X receptor[J]. Journal of Dalian Medical University(大连医科大学学报), 2021, 43(3): 244-250.
[48] YAO ZW, CHEN L, HU M, et al.The discovery of a new potent FXR agonist based on natural product screening[J]. Bioorganic Chemistry, 2023, 143: 106979.
[49] HUO XK, LIU J, YU ZL, et al.Alisma orientale extract exerts the reversing cholestasis effect by activation of farnesoid X receptor[J]. Phytomedicine, 2018, 42: 34-42.
[50] YANG F, WANG Y, LI G, et al.Effects of corilagin on alleviating cholestasis via farnesoid X receptor-associated pathways in vitro and in vivo[J]. British Journal of Pharmacology, 2018, 175(5): 810-829.
[51] RICKETTS ML, BOEKSCHOTEN MV, KREEFT AJ, et al.The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors[J]. Molecular Endocrinology, 2007, 21(7): 1603-1616.
[52] HE XL, ZHOU YY, YU JT, et al.JiaGaSongTang improves chronic cholestasis via enhancing FXR-mediated bile acid metabolism[J]. Phytomedicine, 2024, 128: 155347.
[53] LIU ZX, CHEN L, CHEN MY, et al.Sarmentol H derived from sedum sarmentosum bunge directly targets FXR to mitigate cholestasis by recruiting SRC-1[J]. Phytomedicine, 2024, 130: 155759.
[54] MENG Q, CHEN XL, WANG CY, et al.Protective effects of alisol B 23-acetate from edible botanical Rhizoma alismatis against carbon tetrachloride-induced hepatotoxicity in mice[J]. Food & Function, 2015, 6(4): 1241-1250.
[55] XU J, ZHANG H, CHEN H, et al.Safety, tolerability, pharmacokinetics and pharmacodynamics of a novel farnesoid X receptor (FXR) agonist-TQA3526 in healthy Chinese volunteers: a double-blind, randomized, placebo-controlled, dose-escalation, food effect phase I study[J]. Annals of Medicine, 2023, 55(2): 2264850.
[56] SANYAL AJ, LOPEZ P, LAQITZ EJ, et al.Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial[J]. Nature Medicine, 2023, 29(2): 392-400.
[57] WANG Q, WEN HR, MA SC.Screening of hepatotoxic components in Polygonum multiflorum by taking FXR nuclear receptors as targets[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2022, 19(6): 630-634.