Mechanism of action of bile acid metabolism in regulating cholestatic liver disease and the research and development of drugs

Jing LI; Kuiyang ZHENG; Beibei ZHANG

doi:10.3969/j.issn.1001-5256.2021.10.048

Volume 37 Issue 10

Oct. 2021

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Article Navigation > Journal of Clinical Hepatology > 2021 > 37(10): 2482-2487

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Mechanism of action of bile acid metabolism in regulating cholestatic liver disease and the research and development of drugs

DOI: 10.3969/j.issn.1001-5256.2021.10.048

Department of Pathogenic Biology and Immunology, Xuzhou Medical University; Laboratory of Infection and Immunology, Xuzhou Medical University; Jiangsu Key Laboratory of Immunology and Metabolism, Xuzhou, Jiangsu 221004, China

Research funding:

Natural Science Foundation of Jiangsu Province of China (BK20201011);

Natural Science Foundation of the Jiangsu Higher Education Institutions of China (20KJB310011);

Jiangsu Postdoctoral Science Foundation (RC7062005);

Graduate Research Innovation Plan (KYCX20-2468)

Received Date: 2021-02-05
Accepted Date: 2021-03-08
Published Date: 2021-10-20

Abstract

Abstract

Bile acids are the end products of cholesterol metabolism and are classified as primary bile acids and secondary bile acids. They can promote nutrition absorption and regulate immune response, glucose/lipid/energy metabolism, and microbiota homeostasis by acting on bile acid nuclear receptors and membrane receptors. Cholestatic liver disease (CLD) is a type of liver disease caused by abnormalities of the hepatobiliary system due to cholestasis, with the initial manifestations of hepatocyte and/or bile duct injury, which further leads to abnormal bile acid synthesis, secretion, and excretion. In-depth studies have gradually revealed the role and mechanism of bile acids in CLD, and drugs targeting the action sites of bile acids are under research and development. This article elaborates on the role and mechanism of bile acid metabolism in CLDand summarizes the research and development of drugs for CLD treatment based on bile acid metabolism, so as to provide a reference for future research on the prevention and treatment of CLD.
- Cholestasis,
- Cholic Acids,
- Pathologic Processes,
- Drug Design

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References

[1]	ZHANG QD, LU LG. Mechanisms and treatment of cholestasis- induced liver fibrosis[J]. J Clin Hepatol, 2015, 31(3): 337-341. DOI: 10.3969/j.issn.1001-5256.2015.03.005. 张启迪, 陆伦根. 胆汁淤积致肝纤维化的机制及治疗[J]. 临床肝胆病杂志, 2015, 31(3): 337-341. DOI: 10.3969/j.issn.1001-5256.2015.03.005.
[2]	Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Gastroenterology, Chinese Medical Association; Chinese Society of Infectious Diseases, Chinese Medical Association. Consensus on the diagnosis and treatment of cholestasis liver diseases(2015)[J]. J Clin Hepatol, 2015, 31(12): 1989-1999. DOI: 10.3969/j.issn.1001-5256.2015.12.005. 中华医学会肝病学分会, 中华医学会消化病学分会, 中华医学会感染病学分会. 胆汁淤积性肝病诊断和治疗共识(2015)[J]. 临床肝胆病杂志, 2015, 31(12): 1989-1999. DOI: 10.3969/j.issn.1001-5256.2015.12.005.
[3]	CHIANG J, FERRELL JM. Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy[J]. Am J Physiol Gastrointest Liver Physiol, 2020, 318(3): g554-g573. DOI: 10.1152/ajpgi.00223.2019.
[4]	LI M, CAI SY, BOYER JL. Mechanisms of bile acid mediated inflammation in the liver[J]. Mol Aspects Med, 2017, 56: 45-53. DOI: 10.1016/j.mam.2017.06.001.
[5]	LI XF, GONG JY, WANG JS. Association between enterohepatic circulation of bile acid and cholestatic liver disease[J]. J Clin Hepatol, 2017, 33(10): 1922-1927. DOI: 10.3969/j.issn.1001-5256.2017.10.014. 李晓峰, 龚敬宇, 王建设. 胆汁酸的肠肝循环与胆汁淤积性肝病[J]. 临床肝胆病杂志, 2017, 33(10): 1922-1927. DOI: 10.3969/j.issn.1001-5256.2017.10.014.
[6]	SHEN H, HU M, WEI ZH, et al. Bile formation, secretion, and excretion and the pathogenesis of cholestasis[J]. J Clin Hepatol, 2019, 35(2): 431-437. DOI: 10.3969/j.issn.1001-5256.2019.02.043. 申弘, 胡萌, 魏泽辉, 等. 胆汁的生成、分泌、排泄及胆汁淤积发生机制[J]. 临床肝胆病杂志, 2019, 35(2): 431-437. DOI: 10.3969/j.issn.1001-5256.2019.02.043.
[7]	JANSEN PL, GHALLAB A, VARTAK N, et al. The ascending pathophysiology of cholestatic liver disease[J]. Hepatology, 2017, 65(2): 722-738. DOI: 10.1002/hep.28965.
[8]	CHIANG J, FERRELL JM. Bile acid metabolism in liver pathobiology[J]. Gene Expr, 2018, 18(2): 71-87. DOI: 10.3727/105221618X15156018385515.
[9]	TRAUNER M, FUCHS CD, HALILBASIC E, et al. New therapeutic concepts in bile acid transport and signaling for management of cholestasis[J]. Hepatology, 2017, 65(4): 1393-1404. DOI: 10.1002/hep.28991.
[10]	KEITEL V, DRÖGE C, HÄUSSINGER D. Targeting FXR in cholestasis[J]. Handb Exp Pharmacol, 2019, 256: 299-324. DOI: 10.1007/164_2019_231.
[11]	GULAMHUSEIN AF, HIRSCHFIELD GM. Primary biliary cholangitis: Pathogenesis and therapeutic opportunities[J]. Nat Rev Gastroenterol Hepatol, 2020, 17(2): 93-110. DOI: 10.1038/s41575-019-0226-7.
[12]	PABLO ARAB J, CABRERA D, ARRESE M. Bile acids in cholestasis and its treatment[J]. Ann Hepatol, 2017, 16(Suppl 1): s53-s57. DOI: 10.5604/01.3001. 0010.5497.
[13]	CHEUNG AC, LORENZO PISARELLO MJ, LARUSSO NF. Pathobiology of biliary epithelia[J]. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(4 Pt B): 1220-1231. DOI: 10.1016/j.bbadis.2017.06.024.
[14]	BAIOCCHI L, ZHOU T, LIANGPUNSAKUL S, et al. Dual role of bile acids on the biliary epithelium: Friend or foe?[J]. Int J Mol Sci, 2019, 20(8): 1869. DOI: 10.3390/ijms20081869.
[15]	CARIELLO M, PICCININ E, GARCIA-IRIGOYEN O, et al. Nuclear receptor FXR, bile acids and liver damage: Introducing the progressive familial intrahepatic cholestasis with FXR mutations[J]. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(4 Pt B): 1308-1318. DOI: 10.1016/j.bbadis.2017.09.019.
[16]	IBRAHIM S, DAYOUB R, KRAUTBAUER S, et al. Bile acid-induced apoptosis and bile acid synthesis are reduced by over-expression of Augmenter of Liver Regeneration (ALR) in a STAT3-dependent mechanism[J]. Exp Cell Res, 2019, 374(1): 189-197. DOI: 10.1016/j.yexcr.2018.11.023.
[17]	LI Y, TANG R, LEUNG P, et al. Bile acids and intestinal microbiota in autoimmune cholestatic liver diseases[J]. Autoimmun Rev, 2017, 16(9): 885-896. DOI: 10.1016/j.autrev.2017.07.002.
[18]	O'BRIEN KM, ALLEN KM, ROCKWELL CE, et al. IL-17A synergistically enhances bile acid-induced inflammation during obstructive cholestasis[J]. Am J Pathol, 2013, 183(5): 1498-1507. DOI: 10.1016/j.ajpath.2013.07.019.
[19]	GUO C, XIE S, CHI Z, et al. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome[J]. Immunity, 2016, 45(4): 944. DOI: 10.1016/j.immuni.2016.10.009.
[20]	PANZITT K, FICKERT P, WAGNER M. Regulation of autophagy by bile acids and in cholestasis - CholestoPHAGY or CholeSTOPagy[J]. Biochim Biophys Acta Mol Basis Dis, 2021, 1867(2): 166017. DOI: 10.1016/j.bbadis.2020.166017.
[21]	KIM S, HAN SY, YU KS, et al. Impaired autophagy promotes bile acid-induced hepatic injury and accumulation of ubiquitinated proteins[J]. Biochem Biophys Res Commun, 2018, 495(1): 1541-1547. DOI: 10.1016/j.bbrc.2017.11.202.
[22]	PANZITT K, JUNGWIRTH E, KRONES E, et al. FXR-dependent Rubicon induction impairs autophagy in models of human cholestasis[J]. J Hepatol, 2020, 72(6): 1122-1131. DOI: 10.1016/j.jhep.2020.01.014.
[23]	GAO L, LV G, GUO X, et al. Activation of autophagy protects against cholestasis-induced hepatic injury[J]. Cell Biosci, 2014, 4: 47. DOI: 10.1186/2045-3701-4-47.
[24]	GAO L, LV G, LI R, et al. Glycochenodeoxycholate promotes hepatocellular carcinoma invasion and migration by AMPK/mTOR dependent autophagy activation[J]. Cancer Lett, 2019, 454: 215-223. DOI: 10.1016/j.canlet.2019.04.009.
[25]	GAO X, FU T, WANG C, et al. Computational discovery and experimental verification of farnesoid X receptor agonist auraptene to protect against cholestatic liver injury[J]. Biochem Pharmacol, 2017, 146: 127-138. DOI: 10.1016/j.bcp. 201 7.09.016.
[26]	BYUN S, KIM DH, RYERSON D, et al. Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis[J]. Nat Commun, 2018, 9(1): 2590. DOI: 10.1038/s41467-018-04697-5.
[27]	THOMPSON MD, MOGHE A, CORNUET P, et al. β-Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis[J]. Hepatology, 2018, 67(3): 955-971. DOI: 10.1002/hep.29371.
[28]	LIU Y, CHEN K, LI F, et al. Probiotic lactobacillus rhamnosus GG prevents liver fibrosis through inhibiting hepatic bile acid synthesis and enhancing bile acid excretion in mice[J]. Hepatology, 2020, 71(6): 2050-2066. DOI: 10.1002/hep.30975.
[29]	KEITEL V, STINDT J, HÄUSSINGER D. Bile acid-activated receptors: GPBAR1 (TGR5) and other G protein-coupled receptors[J]. Handb Exp Pharmacol, 2019, 256: 19-49. DOI: 10.1007/164_2019_230.
[30]	KEITEL V, HÄUSSINGER D. Role of TGR5 (GPBAR1) in liver disease[J]. Semin Liver Dis, 2018, 38(4): 333-339. DOI: 10.1055/s-0038-1669940.
[31]	KLINDT C, REICH M, HELLWIG B, et al. The G protein-coupled bile acid receptor TGR5 (Gpbar1) modulates endothelin-1 signaling in liver[J]. Cells, 2019, 8(11): 1467. DOI: 10.3390/cells8111467.
[32]	REICH M, DEUTSCHMANN K, SOMMERFELD A, et al. TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro[J]. Gut, 2016, 65(3): 487-501. DOI: 10.1136/gutjnl-2015-309458.
[33]	ERICE O, LABIANO I, ARBELAIZ A, et al. Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression[J]. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(4 Pt B): 1335-1344. DOI: 10.1016/j.bbadis.2017.08.016.
[34]	RODRIGUES CM, MOSHAGE H. Targeting TGR5 in cholangiocyte proliferation: Default topic[J]. Gut, 2016, 65(3): 369-370. DOI: 10.1136/gutjnl-2015-310812.
[35]	CHEN MJ, LIU C, WAN Y, et al. Enterohepatic circulation of bile acids and their emerging roles on glucolipid metabolism[J]. Steroids, 2021, 165: 108757. DOI: 10.1016/j.steroids.2020.108757.
[36]	WANG Y, GAO X, ZHANG X, et al. Gut microbiota dysbiosis is associated with altered bile acid metabolism in infantile cholestasis[J]. mSystems, 2019, 4(6): e00463-19. DOI: 10.1128/mSystems.00463-19.
[37]	SABINO J, VIEIRA-SILVA S, MACHIELS K, et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD[J]. Gut, 2016, 65(10): 1681-1689. DOI: 10.1136/gutjnl-2015-311004.
[38]	QUIGLEY EM. Primary biliary cirrhosis and the microbiome[J]. Semin Liver Dis, 2016, 36(4): 349-353. DOI: 10.1055/s-0036-1594006.
[39]	RVHLEMANN MC, HEINSEN FA, ZENOUZI R, et al. Faecal microbiota profiles as diagnostic biomarkers in primary sclerosing cholangitis[J]. Gut, 2017, 66(4): 753-754. DOI: 10.1136/gutjnl-2016-312180.
[40]	LIAO L, SCHNEIDER KM, GALVEZ E, et al. Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis[J]. Gut, 2019, 68(8): 1477-1492. DOI: 10.1136/gutjnl-2018-316670.
[41]	TEDESCO D, THAPA M, CHIN CY, et al. Alterations in intestinal microbiota lead to production of interleukin 17 by intrahepatic γδ T-cell receptor-positive cells and pathogenesis of cholestatic liver disease[J]. Gastroenterology, 2018, 154(8): 2178-2193. DOI: 10.1053/j.gastro.2018.02.019.
[42]	ISAACS-TEN A, ECHEANDIA M, MORENO-GONZALEZ M, et al. Intestinal microbiome-macrophage crosstalk contributes to cholestatic liver disease by promoting intestinal permeability in mice[J]. Hepatology, 2020, 72(6): 2090-2108. DOI: 10.1002/hep.31228.
[43]	TERZIROLI BERETTA-PICCOLI B, MIELI-VERGANI G, VERGANI D, et al. The challenges of primary biliary cholangitis: What is new and what needs to be done[J]. J Autoimmun, 2019, 105: 102328. DOI: 10.1016/j.jaut.2019.102328.
[44]	CABRERA D, ARAB JP, ARRESE M. UDCA, NorUDCA, and TUDCA in liver diseases: A review of their mechanisms of action and clinical applications[J]. Handb Exp Pharmacol, 2019, 256: 237-264. DOI: 10.1007/164_2019_241.
[45]	BEUERS U, TRAUNER M, JANSEN P, et al. New paradigms in the treatment of hepatic cholestasis: From UDCA to FXR, PXR and beyond[J]. J Hepatol, 2015, 62(1 Suppl): s25-s37. DOI: 10.1016/j.jhep.2015.02.023.
[46]	CAO Y, XIAO Y, ZHOU K, et al. FXR agonist GW4064 improves liver and intestinal pathology and alters bile acid metabolism in rats undergoing small intestinal resection[J]. Am J Physiol Gastrointest Liver Physiol, 2019, 317(2): g108-g115. DOI: 10.1152/ajpgi.00356.2017.
[47]	BAGHDASARYAN A, CLAUDEL T, GUMHOLD J, et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2^-/- (Abcb4^-/-) mouse cholangiopathy model by promoting biliary HCO₃^- output[J]. Hepatology, 2011, 54(4): 1303-1312. DOI: 10.1002/hep.24537.
[48]	HARRISON SA, RINELLA ME, ABDELMALEK MF, et al. NGM282 for treatment of non-alcoholic steatohepatitis: A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial[J]. Lancet, 2018, 391(10126): 1174-1185. DOI: 10.1016/S0140-6736(18)30474-4.
[49]	DEGIROLAMO C, SABBÀ C, MOSCHETTA A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23[J]. Nat Rev Drug Discov, 2016, 15(1): 51-69. DOI: 10.1038/nrd.2015.9.
[50]	MAYO MJ, WIGG AJ, LEGGETT BA, et al. NGM282 for treatment of patients with primary biliary cholangitis: A multicenter, randomized, double-blind, placebo-controlled trial[J]. Hepatol Commun, 2018, 2(9): 1037-1050. DOI: 10.1002/hep4.1209.

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Mechanism of action of bile acid metabolism in regulating cholestatic liver disease and the research and development of drugs

DOI: 10.3969/j.issn.1001-5256.2021.10.048

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Mechanism of action of bile acid metabolism in regulating cholestatic liver disease and the research and development of drugs

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