Role of bile acid metabolism in the pathogenesis of primary biliary cholangitis

Wanting JIA; Xiaoxiao LIU; Wenlin TAI

doi:10.3969/j.issn.1001-5256.2022.10.031

Volume 38 Issue 10

Oct. 2022

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Role of bile acid metabolism in the pathogenesis of primary biliary cholangitis

DOI: 10.3969/j.issn.1001-5256.2022.10.031

Department of Clinical Laboratory, The Second Affiliated Hospital of Kunming Medical University, Kunming 650032, China

Research funding:

National Natural Science Foundation of China (82060385)

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Corresponding author: TAI Wenlin, taiwenlinlin@sohu.com(ORCID: 0000-0002-8278-929X)
Received Date: 2022-03-01
Accepted Date: 2022-04-15
Published Date: 2022-10-20

Abstract

Abstract

Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by a high incidence rate in middle-aged and elderly women, lymphocyte infiltration in small bile ducts, and cholestasis. Main clinical manifestations include fatigue and pruritus caused by cholestasis. Ursodeoxycholic acid and obeticholic acid are currently approved therapeutic drugs for PBC and exert a therapeutic effect by regulating bile acid metabolism and specifically and effectively improving cholestasis. This article introduces the physiological and pathological changes of bile acids in disease states and summarizes the possible ways in which bile acid metabolism is involved in the pathogenesis of diseases and the current treatment methods for bile acid metabolism. It is pointed out that the changes of bile acid metabolism in PBC are mainly associated with anion exchanger 2 deficiency, innate genetic variation and acquired adaptive changes of bile acid metabolism transporters and nuclear receptors, and changes in the structure of intestinal flora.
- Primary Biliary Cholangitis,
- Bile Acids and Salts,
- Pathologic Processes

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References(54)

References

[1]	LLEO A, WANG GQ, GERSHWIN ME, et al. Primary biliary cholangitis[J]. Lancet, 2020, 396(10266): 1915-1926. DOI: 10.1016/S0140-6736(20)31607-X.
[2]	TRIVEDI PJ, HIRSCHFIELD GM. Recent advances in clinical practice: epidemiology of autoimmune liver diseases[J]. Gut, 2021, 70(10): 1989-2003. DOI: 10.1136/gutjnl-2020-322362.
[3]	ZENG N, DUAN W, CHEN S, et al. Epidemiology and clinical course of primary biliary cholangitis in the Asia-Pacific region: a systematic review and meta-analysis[J]. Hepatol Int, 2019, 13(6): 788-799. DOI: 10.1007/s12072-019-09984-x.
[4]	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.
[5]	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.
[6]	HANG S, PAIK D, YAO L, et al. Bile acid metabolites control TH17 and Treg cell differentiation[J]. Nature, 2019, 576(7785): 143-148. DOI: 10.1038/s41586-019-1785-z.
[7]	SONG X, SUN X, OH SF, et al. Microbial bile acid metabolites modulate gut RORγ⁺ regulatory T cell homeostasis[J]. Nature, 2020, 577(7790): 410-415. DOI: 10.1038/s41586-019-1865-0.
[8]	XIANG J, ZHANG Z, XIE H, et al. Effect of different bile acids on the intestine through enterohepatic circulation based on FXR[J]. Gut Microbes, 2021, 13(1): 1949095. DOI: 10.1080/19490976.2021.1949095.
[9]	WANG Y, LI J, MATYE D, et al. Bile acids regulate cysteine catabolism and glutathione regeneration to modulate hepatic sensitivity to oxidative injury[J]. JCI Insight, 2018, 3(8): e99676. DOI: 10.1172/jci.insight.99676.
[10]	JUNG H, CHEN J, HU X, et al. BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination[J]. JCI Insight, 2020, 6(1): e141640. DOI: 10.1172/jci.insight.141640.
[11]	XIE C, TAKAHASHI S, BROCKER CN, et al. Hepatocyte peroxisome proliferator-activated receptor α regulates bile acid synthesis and transport[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2019, 1864(10): 1396-1411. DOI: 10.1016/j.bbalip.2019.05.014.
[12]	JONES D, BOUDES PF, SWAIN MG, et al. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study[J]. Lancet Gastroenterol Hepatol, 2017, 2(10): 716-726. DOI: 10.1016/S2468-1253(17)30246-7.
[13]	ENHANCE: Safety and efficacy of seladelpar in patients with primary biliary cholangitis-a phase 3, international, randomized, placebo-controlled study[J]. Gastroenterol Hepatol (N Y), 2021, 17(2 Suppl 3): 5-6.
[14]	KREMER AE, MAYO MJ, HIRSCHFIELD G, et al. Seladelpar improved measures of pruritus, sleep, and fatigue and decreased serum bile acids in patients with primary biliary cholangitis[J]. Liver Int, 2022, 42(1): 112-123. DOI: 10.1111/liv.15039.
[15]	XU BY, TANG XD, CHEN J, et al. Rifampicin induces clathrin-dependent endocytosis and ubiquitin-proteasome degradation of MRP2 via oxidative stress-activated PKC-ERK/JNK/p38 and PI3K signaling pathways in HepG2 cells[J]. Acta Pharmacol Sin, 2020, 41(1): 56-64. DOI: 10.1038/s41401-019-0266-0.
[16]	SONODA J, CHONG LW, DOWNES M, et al. Pregnane X receptor prevents hepatorenal toxicity from cholesterol metabolites[J]. Proc Natl Acad Sci U S A, 2005, 102(6): 2198-2203. DOI: 10.1073/pnas.0409481102.
[17]	KHURANA S, SINGH P. Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials[J]. Liver Int, 2006, 26(8): 943-948. DOI: 10.1111/j.1478-3231.2006.01326.x.
[18]	SULTANA H, KOMAI M, SHIRAKAWA H. The role of vitamin K in cholestatic liver disease[J]. Nutrients, 2021, 13(8): 2515. DOI: 10.3390/nu13082515.
[19]	ZHANG Z, CHEN F, LI J, et al. 1, 25(OH)2D3 suppresses proinflammatory responses by inhibiting Th1 cell differentiation and cytokine production through the JAK/STAT pathway[J]. Am J Transl Res, 2018, 10(8): 2737-2746.
[20]	FANG F, WANG J, PAN J, et al. Relationship between vitamin D (1, 25-dihydroxyvitamin D3) receptor gene polymorphisms and primary biliary cirrhosis risk: a meta-analysis[J]. Genet Mol Res, 2015, 14(1): 981-988. DOI: 10.4238/2015.February.6.1.
[21]	KEMPINSKA-PODHORODECKA A, MILKIEWICZ M, WASIK U, et al. Decreased expression of vitamin D receptor affects an immune response in primary biliary cholangitis via the VDR-miRNA155-SOCS1 pathway[J]. Int J Mol Sci, 2017, 18(2): 289. DOI: 10.3390/ijms18020289.
[22]	GONZALEZ-SANCHEZ E, EL MOURABIT H, JAGER M, et al. Cholangiopathy aggravation is caused by VDR ablation and alleviated by VDR-independent vitamin D signaling in ABCB4 knockout mice[J]. Biochim Biophys Acta Mol Basis Dis, 2021, 1867(4): 166067. DOI: 10.1016/j.bbadis.2020.166067.
[23]	VASSILEVA G, GOLOVKO A, MARKOWITZ L, et al. Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation[J]. Biochem J, 2006, 398(3): 423-430. DOI: 10.1042/BJ20060537.
[24]	FIORUCCI S, DISTRUTTI E, CARINO A, et al. Bile acids and their receptors in metabolic disorders[J]. Prog Lipid Res, 2021, 82: 101094. DOI: 10.1016/j.plipres.2021.101094.
[25]	SANG C, WANG X, ZHOU K, et al. Bile acid profiles are distinct among patients with different etiologies of chronic liver disease[J]. J Proteome Res, 2021, 20(5): 2340-2351. DOI: 10.1021/acs.jproteome.0c00852.
[26]	CHEN W, WEI Y, XIONG A, et al. Comprehensive analysis of serum and fecal bile acid profiles and interaction with gut microbiota in primary biliary cholangitis[J]. Clin Rev Allergy Immunol, 2020, 58(1): 25-38. DOI: 10.1007/s12016-019-08731-2.
[27]	PRIETO J, QIAN C, GARCÍA N, et al. Abnormal expression of anion exchanger genes in primary biliary cirrhosis[J]. Gastroenterology, 1993, 105(2): 572-578. DOI: 10.1016/0016-5085(93)90735-u.
[28]	MEDINA JF, MARTÍNEZ-ANSÓ, VAZQUEZ JJ, et al. Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis[J]. Hepatology, 1997, 25(1): 12-17. DOI: 10.1002/hep.510250104.
[29]	BANALES JM, SÁEZ E, URIZ M, et al. Up-regulation of microRNA 506 leads to decreased Cl^-/HCO₃^- anion exchanger 2 expression in biliary epithelium of patients with primary biliary cirrhosis[J]. Hepatology, 2012, 56(2): 687-697. DOI: 10.1002/hep.25691.
[30]	RODRIGUES PM, PERUGORRIA MJ, SANTOS-LASO A, et al. Primary biliary cholangitis: A tale of epigenetically-induced secretory failure?[J]. J Hepatol, 2018, 69(6): 1371-1383. DOI: 10.1016/j.jhep.2018.08.020.
[31]	HISAMOTO S, SHIMODA S, HARADA K, et al. Hydrophobic bile acids suppress expression of AE2 in biliary epithelial cells and induce bile duct inflammation in primary biliary cholangitis[J]. J Autoimmun, 2016, 75: 150-160. DOI: 10.1016/j.jaut.2016.08.006.
[32]	KOJIMA H, NIES AT, KÖNIG J, et al. Changes in the expression and localization of hepatocellular transporters and radixin in primary biliary cirrhosis[J]. J Hepatol, 2003, 39(5): 693-702. DOI: 10.1016/s0168-8278(03)00410-0.
[33]	INAMINE T, HIGA S, NOGUCHI F, et al. Association of genes involved in bile acid synthesis with the progression of primary biliary cirrhosis in Japanese patients[J]. J Gastroenterol, 2013, 48(10): 1160-1170. DOI: 10.1007/s00535-012-0730-9.
[34]	PHAM DH, KUDIRA R, XU L, et al. Deleterious variants in ABCC12 are detected in idiopathic chronic cholestasis and cause intrahepatic bile duct loss in model organisms[J]. Gastroenterology, 2021, 161(1): 287-300. e16. DOI: 10.1053/j.gastro.2021.03.026.
[35]	AFONSO MB, RODRIGUES PM, SIMÃO AL, et al. miRNA-21 ablation protects against liver injury and necroptosis in cholestasis[J]. Cell Death Differ, 2018, 25(5): 857-872. DOI: 10.1038/s41418-017-0019-x.
[36]	JUANOLA O, HASSAN M, KUMAR P, et al. Intestinal microbiota drives cholestasis-induced specific hepatic gene expression patterns[J]. Gut Microbes, 2021, 13(1): 1-20. DOI: 10.1080/19490976.2021.1911534.
[37]	WANG D, DOESTZADA M, CHEN L, et al. Characterization of gut microbial structural variations as determinants of human bile acid metabolism[J]. Cell Host Microbe, 2021, 29(12): 1802-1814. e5. DOI: 10.1016/j.chom.2021.11.003.
[38]	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.
[39]	HARUTA I, HASHIMOTO E, KATO Y, et al. Lipoteichoic acid may affect the pathogenesis of bile duct damage in primary biliary cirrhosis[J]. Autoimmunity, 2006, 39(2): 129-135. DOI: 10.1080/08916930600623841.
[40]	TANG R, WEI Y, LI Y, et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy[J]. Gut, 2018, 67(3): 534-541. DOI: 10.1136/gutjnl-2016-313332.
[41]	LI B, ZHANG J, CHEN Y, et al. Alterations in microbiota and their metabolites are associated with beneficial effects of bile acid sequestrant on icteric primary biliary cholangitis[J]. Gut Microbes, 2021, 13(1): 1946366. DOI: 10.1080/19490976.2021.1946366.
[42]	HARMS MH, VAN BUUREN HR, CORPECHOT C, et al. Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis[J]. J Hepatol, 2019, 71(2): 357-365. DOI: 10.1016/j.jhep.2019.04.001.
[43]	XIA ZY, HAN T, MENG HJ. Clinical efficacy of early stage immunosuppression combined with ursodeoxycholic acid in the treatment of primary biliary cirrhosis[J]. Clin J Med Offic, 2020, 48(1): 97-98, 101. DOI: 10.16680/j.1671-3826.2020.01.33. 夏志勇, 韩涛, 孟红军. 早期免疫抑制联合熊去氧胆酸治疗原发性胆汁性肝硬化临床疗效[J]. 临床军医杂志, 2020, 48(1): 97-98, 101. DOI: 10.16680/j.1671-3826.2020.01.33.
[44]	KULKARNI AV, TEVETHIA HV, ARAB JP, et al. Efficacy and safety of obeticholic acid in liver disease-A systematic review and meta-analysis[J]. Clin Res Hepatol Gastroenterol, 2021, 45(3): 101675. DOI: 10.1016/j.clinre.2021.101675.
[45]	KJÆRGAARD K, FRISCH K, SØRENSEN M, et al. Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis[J]. J Hepatol, 2021, 74(1): 58-65. DOI: 10.1016/j.jhep.2020.07.028.
[46]	GOMEZ E, GARCIA BUEY L, MOLINA E, et al. Effectiveness and safety of obeticholic acid in a Southern European multicentre cohort of patients with primary biliary cholangitis and suboptimal response to ursodeoxycholic acid[J]. Aliment Pharmacol Ther, 2021, 53(4): 519-530. DOI: 10.1111/apt.16181.
[47]	VERBEKE L, NEVENS F, LALEMAN W. Steroidal or non-steroidal FXR agonists - Is that the question?[J]. J Hepatol, 2017, 66(4): 680-681. DOI: 10.1016/j.jhep.2017.01.013.
[48]	JOHN BV, SCHWARTZ K, LEVY C, et al. Impact of obeticholic acid exposure on decompensation and mortality in primary biliary cholangitis and cirrhosis[J]. Hepatol Commun, 2021, 5(8): 1426-1436. DOI: 10.1002/hep4.1720.
[49]	CHEN J, GU J, SHAH B, et al. Pharmacokinetics of tropifexor, a potent farnesoid X receptor agonist, in participants with varying degrees of hepatic impairment[J]. J Clin Pharmacol, 2022, 62(4): 520-531. DOI: 10.1002/jcph.1996.
[50]	FENG BL, YU HH, SHEN W. Ursodeoxycholic acid combined with bezafibrate in the treatment of refractory primary biliary cholangitis: a meta-analysis[J]. Chin J Hepatol, 2019, 27(4): 304-311. DOI: 10.3760/cma.j.issn.1007-3418.2019.04.012. 奉白蕾, 俞慧宏, 沈薇. 熊去氧胆酸联合苯扎贝特治疗难治性原发性胆汁性胆管炎的Meta分析[J]. 中华肝脏病杂志, 2019, 27(4): 304-311. DOI: 10.3760/cma.j.issn.1007-3418.2019.04.012.
[51]	SCHATTENBERG JM, PARES A, KOWDLEY KV, et al. A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA[J]. J Hepatol, 2021, 74(6): 1344-1354. DOI: 10.1016/j.jhep.2021.01.013.
[52]	KIM KY, MANCANO MA. Fenofibrate potentiates warfarin effects[J]. Ann Pharmacother, 2003, 37(2): 212-215. DOI: 10.1177/106002800303700210.
[53]	FILIPPATOS TD, ELISAF MS. Safety considerations with fenofibrate/simvastatin combination[J]. Expert Opin Drug Saf, 2015, 14(9): 1481-1493. DOI: 10.1517/14740338.2015.1056778.
[54]	GHONEM NS, ASSIS DN, BOYER JL. Fibrates and cholestasis[J]. Hepatology, 2015, 62(2): 635-643. DOI: 10.1002/hep.27744.

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Role of bile acid metabolism in the pathogenesis of primary biliary cholangitis

DOI: 10.3969/j.issn.1001-5256.2022.10.031

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Role of bile acid metabolism in the pathogenesis of primary biliary cholangitis

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