基因突变致胆汁酸代谢异常相关发生机制的研究进展

易波; 李雪; 汤善宏

doi:10.3969/j.issn.1001-5256.2022.09.036

基因突变致胆汁酸代谢异常相关发生机制的研究进展

DOI: 10.3969/j.issn.1001-5256.2022.09.036

易波^{1, 2},
李雪^{2, 3},
汤善宏^2, , ,

1.
成都医学院，成都 610500
2.
中国人民解放军西部战区总医院消化内科，成都 610083
3.
成都中医药大学医学与生命科学学院，成都 610072

基金项目:

四川省卫生健康委员会科研课题 (20PJ180)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：易波参与分析相关领域文献，文章撰写及修改；李雪参与文章结构及部分内容修改；汤善宏负责拟定写作题目，指导撰写文章与最后定稿。

详细信息

通信作者:
汤善宏，15928956390@163.com

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- 被引次数: 0
出版历程
- 收稿日期: 2022-02-22
- 录用日期: 2022-04-28
- 出版日期: 2022-09-20

Research advances in the mechanism of abnormal bile acid metabolism caused by gene mutation

Bo YI^{1, 2},
Xue LI^{2, 3},
Shanhong TANG^{2
, ,
,}

1.
Chengdu Medical College, Chengdu 610500, China
2.
Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu 610083, China
3.
School of Medicine and Life Science, Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China

More Information

Corresponding author: TANG Shanhong, 15928956390@163.com(ORCID: 0000-0001-6652-2942)

摘要

摘要: 胆汁酸由肝脏合成并分解代谢，诸多原因均可导致其生成、分泌及重吸收障碍，进而引起体内胆汁酸代谢异常。常见诱因包括肝炎、病毒、酒精、药物、胆道梗阻及遗传等。目前已有研究报道胆汁酸代谢异常与转运蛋白基因突变存在联系，国内外对此均进行了深入研究。本文主要对基因突变所致胆汁酸代谢异常的发生机制及相关研究进展作一综述，为阐明此类疾病的诊断和治疗提供新依据及新思路。
- 胆汁酸类和盐类 /
- 胆汁淤积 /
- 代谢 /
- 突变
Abstract: Bile acids are synthesized and catabolized by the liver, and many factors can lead to disorders in the production, secretion, and reabsorption of bile acids, thereby causing abnormal bile acid metabolism in vivo. Common predisposing factors include hepatitis, viruses, alcohol, drugs, biliary obstruction, and inheritance. It has been reported that abnormal bile acid metabolism is associated with transporter gene mutation, and in-depth studies have been conducted in China and globally. This article reviews the mechanism of abnormal bile acid metabolism caused by gene mutations and related research advances, so as to provide a new basis and new ideas for the diagnosis and treatment of such diseases.
- Bile Acids and Salts /
- Cholestasis /
- Metabolism /
- Mutation

HTML全文

图 1 胆汁酸合成、代谢及治疗靶点示意图

Figure 1. Schematic diagram of bile acid synthesis, metabolism and therapeutic target

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参考文献(45)

[1]	CASTRO RE, RODRIGUES C. Cell death and microRNAs in cholestatic liver diseases: Update on potential therapeutic applications[J]. Curr Drug Targets, 2017, 18(8): 921-931. DOI: 10.2174/1389450116666151019102358.
[2]	YANG Y, ZHANG J. Bile acid metabolism and circadian rhythms[J]. Am J Physiol Gastrointest Liver Physiol, 2020, 319(5): G549-G563. DOI: 10.1152/ajpgi.00152.2020.
[3]	CHIANG J, FERRELL JM. Bile acid metabolism in liver pathobiology[J]. Gene Expr, 2018, 18(2): 71-87. DOI: 10.3727/105221618X15156018385515.
[4]	JIA W, WEI M, RAJANI C, et al. Targeting the alternative bile acid synthetic pathway for metabolic diseases[J]. Protein Cell, 2021, 12(5): 411-425. DOI: 10.1007/s13238-020-00804-9.
[5]	TICHO AL, MALHOTRA P, DUDEJA PK, et al. Intestinal absorption of bile acids in health and disease[J]. Compr Physiol, 2019, 10(1): 21-56. DOI: 10.1002/cphy.c190007.
[6]	ULZURRUN E, STEPHENS C, CRESPO E, et al. Role of chemical structures and the 1331T > C bile salt export pump polymorphism in idiosyncratic drug-induced liver injury[J]. Liver Int, 2013, 33(9): 1378-1385. DOI: 10.1111/liv.12193.
[7]	NAYAGAM JS, WILLIAMSON C, JOSHI D, et al. Review article: liver disease in adults with variants in the cholestasis-related genes ABCB11, ABCB4 and ATP8B1[J]. Aliment Pharmacol Ther, 2020, 52(11-12): 1628-1639. DOI: 10.1111/apt.16118.
[8]	JETTER A, KULLAK-UBLICK GA. Drugs and hepatic transporters: A review[J]. Pharmacol Res, 2020, 154: 104234. DOI: 10.1016/j.phrs.2019.04.018.
[9]	DRÖGE C, BONUS M, BAUMANN U, et al. Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants[J]. J Hepatol, 2017, 67(6): 1253-1264. DOI: 10.1016/j.jhep.2017.07.004.
[10]	FERREBEE CB, LI J, HAYWOOD J, et al. Organic solute transporter α-β protects ileal enterocytes from bile acid-induced injury[J]. Cell Mol Gastroenterol Hepatol, 2018, 5(4): 499-522. DOI: 10.1016/j.jcmgh.2018.01.006.
[11]	XIAO L, PAN G. An important intestinal transporter that regulates the enterohepatic circulation of bile acids and cholesterol homeostasis: The apical sodium-dependent bile acid transporter (SLC10A2/ASBT)[J]. Clin Res Hepatol Gastroenterol, 2017, 41(5): 509-515. DOI: 10.1016/j.clinre.2017.02.001.
[12]	van de PEPPEL IP, VERKADE HJ, JONKER JW. Metabolic consequences of ileal interruption of the enterohepatic circulation of bile acids[J]. Am J Physiol Gastrointest Liver Physiol, 2020, 319(5): G619-G625. DOI: 10.1152/ajpgi.00308.2020.
[13]	CHANG ZP, SHAO YY, CHENG Y, rt al. Research progress on expression regulation of apical sodium-dependent cholic acid transporter and its role in the pathogenesis of cholestatic diseases[J]. Shandong Med J, 2018, 58(23): 104-107. DOI: 10.3969/j.issn.1002-266X.2018.23.031. 常壮鹏, 邵云云, 程瑶, 等. 顶端钠依赖性胆酸转运体表达调控及在胆汁淤积性疾病发病中作用的研究进展[J]. 山东医药, 2018, 58(23): 104-107. DOI: 10.3969/j.issn.1002-266X.2018.23.031.
[14]	MALINEN MM, ALI I, BEZENÇON J, et al. Organic solute transporter OSTα/β is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury[J]. Am J Physiol Gastrointest Liver Physiol, 2018, 314(5): G597-G609. DOI: 10.1152/ajpgi.00310.2017.
[15]	BEAUDOIN JJ, BEZENÇON J, SJÖSTEDT N, et al. Role of organic solute transporter alpha/beta in hepatotoxic bile acid transport and drug interactions[J]. Toxicol Sci, 2020, 176(1): 34-35. DOI: 10.1093/toxsci/kfaa052.
[16]	BEAUDOIN JJ, BROUWER K, MALINEN MM. Novel insights into the organic solute transporter alpha/beta, OSTα/β: From the bench to the bedside[J]. Pharmacol Ther, 2020, 211: 107542. DOI: 10.1016/j.pharmthera.2020.107542.
[17]	GAO E, CHEEMA H, WAHEED N, et al. Organic solute transporter alpha deficiency: a disorder with cholestasis, liver fibrosis, and congenital diarrhea[J]. Hepatology, 2020, 71(5): 1879-1882. DOI: 10.1002/hep.31087.
[18]	SULTAN M, RAO A, ELPELEG O, et al. Organic solute transporter-β (SLC51B) deficiency in two brothers with congenital diarrhea and features of cholestasis[J]. Hepatology, 2018, 68(2): 590-598. DOI: 10.1002/hep.29516.
[19]	DAWSON PA. Roles of ileal ASBT and OSTα-OSTβ in regulating bile acid signaling[J]. Dig Dis, 2017, 35(3): 261-266. DOI: 10.1159/000450987.
[20]	ANWER MS, STIEGER B. Sodium-dependent bile salt transporters of the SLC10A transporter family: more than solute transporters[J]. Pflugers Arch, 2014, 466(1): 77-89. DOI: 10.1007/s00424-013-1367-0.
[21]	LU X, LIU L, SHAN W, et al. The role of the sodium-taurocholate co-transporting polypeptide (NTCP) and bile salt export pump (BSEP) in related liver disease[J]. Curr Drug Metab, 2019, 20(5): 377-389. DOI: 10.2174/1389200220666190426152830.
[22]	VAZ FM, PAULUSMA CC, HUIDEKOPER H, et al. Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype[J]. Hepatology, 2015, 61(1): 260-267. DOI: 10.1002/hep.27240.
[23]	LI H, DENG M, GUO L, et al. Clinical and molecular characterization of four patients with NTCP deficiency from two unrelated families harboring the novel SLC10A1 variant c. 595A > C (p. Ser199Arg)[J]. Mol Med Rep, 2019, 20(6): 4915-4924. DOI: 10.3892/mmr.2019.10763.
[24]	BASEL-SALMON L, ORENSTEIN N, MARKUS-BUSTANI K, et al. Improved diagnostics by exome sequencing following raw data reevaluation by clinical geneticists involved in the medical care of the individuals tested[J]. Genet Med, 2019, 21(6): 1443-1451. DOI: 10.1038/s41436-018-0343-7.
[25]	MAO F, LIU T, HOU X, et al. Increased sulfation of bile acids in mice and human subjects with sodium taurocholate cotransporting polypeptide deficiency[J]. J Biol Chem, 2019, 294(31): 11853-11862. DOI: 10.1074/jbc.RA118.007179.
[26]	TAN HJ, DENG M, QIU JW, et al. Monozygotic twins suffering from sodium taurocholate cotransporting polypeptide deficiency: a case report[J]. Front Pediatr, 2018, 6: 354. DOI: 10.3389/fped.2018.00354.
[27]	DONG C, ZHANG BP, WANG H, et al. Clinical and histopathologic features of sodium taurocholate cotransporting polypeptide deficiency in pediatric patients[J]. Medicine (Baltimore), 2019, 98(39): e17305. DOI: 10.1097/MD.0000000000017305.
[28]	TANG SH, ZENG WZ, ZENG JM, et al. A case of Rotor syndrome[J]. Chin Hepatol, 2016, 21(3): 231-232. DOI: 10.3969/j.issn.1008-1704.2016.03.022. 汤善宏, 曾维政, 曾建梅, 等. Rotor综合征1例[J]. 肝脏, 2016, 21(3): 231-232. DOI: 10.3969/j.issn.1008-1704.2016.03.022.
[29]	SCHNEIDER AL, KÖHLER H, RÖTHLISBERGER B, et al. Sodium taurocholate co-transporting polypeptide deficiency[J]. Clin Res Hepatol Gastroenterol, 2022, 46(3): 101824. DOI: 10.1016/j.clinre.2021.101824.
[30]	CLARE KE, MILLER MH, DILLON JF. Genetic factors influencing drug-induced liver injury: Do they have a role in prevention and diagnosis?[J]. Curr Hepatol Rep, 2017, 16(3): 258-264. DOI: 10.1007/s11901-017-0363-9.
[31]	FAN WL, SHIAO MS, HUI RC, et al. HLA association with drug-induced adverse reactions[J]. J Immunol Res, 2017, 2017: 3186328. DOI: 10.1155/2017/3186328.
[32]	CORDELL HJ, HAN Y, MELLS GF, et al. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways[J]. Nat Commun, 2015, 6: 8019. DOI: 10.1038/ncomms9019.
[33]	MA WY, DENG ZH. Current status of immunogenetic studies on primary biliary cholangitis[J]. J Clin Hepatol, 2020, 36(4): 932-935. DOI: 10.3969/j.issn.1001-5256.2020.04.050. 马伟煜, 邓志华. 原发性胆汁性胆管炎的免疫遗传研究现状[J]. 临床肝胆病杂志, 2020, 36(4): 932-935. DOI: 10.3969/j.issn.1001-5256.2020.04.050.
[34]	WANG MJ, ZHONG XM, MA X, et al. Clinical characteristics and gene variants of patients with infantile intrahepatic cholestasis[J]. Chin J Contemp Pediatr, 2021, 23(1): 91-97. DOI: 10.7499/j.issn.1008-8830.2009079. 王美娟, 钟雪梅, 马昕, 等. 婴儿肝内胆汁淤积症患儿的临床特征及基因分析[J]. 中国当代儿科杂志, 2021, 23(1): 91-97. DOI: 10.7499/j.issn.1008-8830.2009079.
[35]	AMIRNENI S, HAEP N, GAD MA, et al. Molecular overview of progressive familial intrahepatic cholestasis[J]. World J Gastroenterol, 2020, 26(47): 7470-7484. DOI: 10.3748/wjg.v26.i47.7470.
[36]	TRAMPERT DC, van de GRAAF S, JONGEJAN A, et al. Hepatobiliary acid-base homeostasis: Insights from analogous secretory epithelia[J]. J Hepatol, 2021, 74(2): 428-441. DOI: 10.1016/j.jhep.2020.10.010.
[37]	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.
[38]	European Association for the Study of the Liver (EASL). EASL clinical practice guidelines on the prevention, diagnosis and treatment of gallstones[J]. J Hepatol, 2016, 65(1): 146-181. DOI: 10.1016/j.jhep.2016.03.005.
[39]	BICOCCA MJ, SPERLING JD, CHAUHAN SP. Intrahepatic cholestasis of pregnancy: Review of six national and regional guidelines[J]. Eur J Obstet Gynecol Reprod Biol, 2018, 231: 180-187. DOI: 10.1016/j.ejogrb.2018.10.041.
[40]	YUAN Z, WANG G, QU J, et al. 9-cis-retinoic acid elevates MRP3 expression by inhibiting sumoylation of RXRα to alleviate cholestatic liver injury[J]. Biochem Biophys Res Commun, 2018, 503(1): 188-194. DOI: 10.1016/j.bbrc.2018.06.001.
[41]	HE H, MENNONE A, BOYER JL, et al. Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct-ligated rats and human hepatic cells[J]. Hepatology, 2011, 53(2): 548-557. DOI: 10.1002/hep.24047.
[42]	BAGHDASARYAN A, FUCHS CD, ÖSTERREICHER CH, et al. Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis[J]. J Hepatol, 2016, 64(3): 674-681. DOI: 10.1016/j.jhep.2015.10.024.
[43]	ERICE O, MUNOZ-GARRIDO P, VAQUERO J, et al. MicroRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation[J]. Hepatology, 2018, 67(4): 1420-1440. DOI: 10.1002/hep.29533.
[44]	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.
[45]	BOSMA PJ, WITS M, OUDE-ELFERINK RP. Gene therapy for progressive familial intrahepatic cholestasis: current progress and future prospects[J]. Int J Mol Sci, 2020, 22(1): 273. DOI: 10.3390/ijms22010273.