ATP结合盒转运体G5/8（ABCG5/8）在胆囊胆固醇结石形成及治疗中的作用

卢琴; 刘卫辉

doi:10.3969/j.issn.1001-5256.2023.09.033

ATP结合盒转运体G5/8（ABCG5/8）在胆囊胆固醇结石形成及治疗中的作用

DOI: 10.3969/j.issn.1001-5256.2023.09.033

卢琴^{1, 2},
刘卫辉^{1, 2, , ,}

1.
电子科技大学医学院，成都 611731
2.
四川省医学科学院·四川省人民医院消化内科，成都 610072

基金项目:

四川省科技厅重点研发项目 (2021YFS0375)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：卢琴负责查阅文献，撰写论文；刘卫辉指导文章撰写及修改、审阅论文。

详细信息

通信作者:
刘卫辉， audiliu12@163.com （ORCID： 0000－0003－2871－8316）

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出版历程
- 收稿日期: 2022-12-11
- 录用日期: 2023-01-19
- 出版日期: 2023-09-19

Research advances in ATP－binding cassette transporter G5/8 and cholesterol gallstones

Qin LU^{1, 2},
Weihui LIU^{1, 2
, ,
,}

1.
School of Medicine，University of Electronic Science and Technology of China，Chengdu 611731，China
2.
Department of Gastroenterology and Hepatology，Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital，Chengdu 610072，China

Research funding:

Key Project of Science and Technology Department of Sichuan Province (2021YFS0375)

More Information

Corresponding author: LIU Weihui， audiliu12@163.com （ORCID： 0000－0003－2871－8316）

摘要

摘要: 胆固醇结石是胆囊结石患者的常见类型，且受多种因素影响。近年来，遗传学因素在胆囊结石中研究广泛，尤其在胆固醇结石形成机制中的作用成为当前研究的热点。ATP结合盒转运体（ABC）是人体内最大的膜转运蛋白家族，在维持脂质和甾醇平衡中发挥着关键功能。ABCG5/8是胆固醇转运蛋白，参与调节体内胆固醇水平，被认为是人体胆固醇结石的主要遗传易感因素。本文讨论了ABCG5/8在胆囊胆固醇结石形成中作用的相关研究进展，并介绍了靶向ABCG5/8治疗胆固醇结石的可能性，为胆固醇结石的病因探究及临床治疗提供一定的理论依据。
- ATP结合盒转运体 /
- 胆囊结石病 /
- 治疗学 /
- 疾病遗传易感性
Abstract: Cholesterol stone is a common type of gallstones and is affected by a variety of controllable and uncontrollable factors. In recent years， extensive studies have been conducted on genetic factors， especially their role in the formation mechanism of cholesterol stones. The ATP－binding cassette family is the largest membrane transporter family in human and plays a key role in maintaining lipid and sterol homeostasis. ATP－binding cassette transporter G5/8 （ABCG5/8） is a cholesterol transporter that participates in the regulation of cholesterol levels in the body and is considered the main genetic susceptibility factor for cholesterol gallstones in humans. This article reviews the research advances in ABCG5/8 in the formation of cholesterol gallstones and introduces the possibility of targeting ABCG5/8 in the treatment of cholesterol gallstones， in order to provide a certain theoretical basis for investigating the etiology and clinical treatment of cholesterol gallstones.
- ATP－binding Cassette /
- Cholecystolithiasis /
- Therapeutics /
- Genetic Predisposition to Disease

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参考文献(49)

[1]	PORTINCASA P, MOSCHETTA A, PALASCIANO G. Cholesterol gallstone disease[J]. Lancet, 2006, 368( 9531): 230－ 239. DOI: 10.1016/S0140－6736(06)69044－2.
[2]	XU ZH, SUN L, HU W. Analysis of efficacy and safety of laparoscopic treatment of acute pancre-atitis by cholecystolithiasis at different operative times[J]. China Med Herald, 2021, 18( 13): 76- 79. 徐梓恒, 孙磊, 胡伟. 不同手术时机运用腹腔镜治疗胆囊结石所致急性胰腺炎的效果及安全性分析[J]. 中国医药导报, 2021, 38( 13): 76－ 79.
[3]	DI CIAULA A, PORTINCASA P. Recent advances in understanding and managing cholesterol gallstones[J]. F1000Res, 2018, 7: F1000 Faculty Rev－ 1529. DOI: 10.12688/f1000research.15505.1.
[4]	LAM R, ZAKKO A, PETROV JC, et al. Gallbladder disorders: a comprehensive review[J]. Dis Mon, 2021, 67( 7): 101130. DOI: 10.1016/j.disamonth.2021.101130.
[5]	di CIAULA A, GARRUTI G, FRÜHBECK G, et al. The role of diet in the pathogenesis of cholesterol gallstones[J]. Curr Med Chem, 2019, 26( 19): 3620－ 3638. DOI: 10.2174/0929867324666170530080636.
[6]	SUN H, WARREN J, YIP J, et al. Factors influencing gallstone formation: a review of the literature[J]. Biomolecules, 2022, 12( 4): 550. DOI: 10.3390/biom12040550.
[7]	ATTRI MR, KUMAR IA, DIN FMU, et al. Pathophysiology of gallstones[M]. Gallstones－Review and Recent Progress, Intech Open, 2021.
[8]	DUO XY, ZHANG SJ, ZHANG HW, et al. Association between gallstones and metabolic syndrome in southern Xinjiang, China[J]. J Clin Hepatol, 2022, 38( 8): 1859－ 1864. DOI: 10.3969/j.issn.1001－5256.2022.08.026. 多小勇, 张示杰, 张宏伟, 等. 南疆地区胆囊结石与代谢综合征的关联性分析[J]. 临床肝胆病杂志, 2022, 38( 8): 1859－ 1864. DOI: 10.3969/j.issn.1001－5256.2022.08.026.
[9]	FENG C, LUO H, WAN LH, et al. Current status of drug treatment for gallbladder stones[J]. Clin J Med Offic, 2022, 50( 5): 544－ 546. DOI: 10.16680/j.1671－3826.2022.05.28. 冯矗, 罗浩, 万柳华, 等. 胆囊结石药物治疗现状[J]. 临床军医杂志, 2022, 50( 5): 544－ 546. DOI: 10.16680/j.1671－3826.2022.05.28.
[10]	QIAO T, MA RH, LUO XB, et al. The systematic classification of gallbladder stones[J]. PLoS One, 2013, 8( 10): e74887. DOI: 10.1371/journal.pone.0074887.
[11]	ZHAO HD, GAO P, ZHAN L. The mechanism of intestinal flora and its metabolites in the formation of cholesterol gallstones[J]. J Clin Hepatol, 2022, 38( 4): 947－ 950. DOI: 10.3969/j.issn.1001－5256.2022.04.042. 赵瀚东, 高鹏, 詹丽. 肠道菌群及其代谢物在胆囊胆固醇结石形成中的作用机制[J]. 临床肝胆病杂志, 2022, 38( 4): 947－ 950. DOI: 10.3969/j.issn.1001－5256.2022.04.042.
[12]	KIM HJ, KIM JS, OH S, et al. Inhibition of ceramide decreased the expression of ATP－binding cassette transporter G5/8 mRNA in an animal model of cholesterol gallstone[J]. Dig Dis, 2017, 35( 5): 439－ 443. DOI: 10.1159/000465517.
[13]	FERKINGSTAD E, ODDSSON A, GRETARSDOTTIR S, et al. Genome－wide association meta－analysis yields 20 loci associated with gallstone disease[J]. Nat Commun, 2018, 9( 1): 5101. DOI: 10.1038/s41467－018－07460－y.
[14]	HU H, SHAO W, LIU Q, et al. Gut microbiota promotes cholesterol gallstone formation by modulating bile acid composition and biliary cholesterol secretion[J]. Nat Commun, 2022, 13( 1): 252. DOI: 10.1038/s41467－021－27758－8.
[15]	WEBER SN, BOPP C, KRAWCZYK M, et al. Genetics of gallstone disease revisited: updated inventory of human lithogenic genes[J]. Curr Opin Gastroenterol, 2019, 35( 2): 82－ 87. DOI: 10.1097/MOG.0000000000000511.
[16]	LIANG KW, HUANG HH, WANG L, et al. Risk of gallstones based on ABCG8 rs11887534 single nucleotide polymorphism among Taiwanese men and women[J]. BMC Gastroenterol, 2021, 21( 1): 468. DOI: 10.1186/s12876－021－02060－5.
[17]	KATSIKA D, MAGNUSSON P, KRAWCZYK M, et al. Gallstone disease in Swedish twins: risk is associated with ABCG8 D19H genotype[J]. J Intern Med, 2010, 268( 3): 279－ 285. DOI: 10.1111/j.1365－2796.2010.02249.x.
[18]	GONG H. Retrospective analysis of gallstone and study of the association between Tibetan and Han patients with gallstones and ABCG5/8 gene polymorphism in Qinghai[D]. Xining: Qinghai University, 2020. 龚浩. 青海地区胆囊结石病例分析及藏、汉族胆囊结石与ABCG5/8基因多态性关联的研究[D]. 西宁: 青海大学, 2020.
[19]	KERR ID, HUTCHISON E, GERARD L, et al. Mammalian ABCG－transporters, sterols and lipids: To bind perchance to transport?[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2021, 1866( 3): 158860. DOI: 10.1016/j.bbalip.2020.158860.
[20]	XAVIER BM, JENNINGS WJ, ZEIN AA, et al. Structural snapshot of the cholesterol－transport ATP－binding cassette proteins 1[J]. Biochem Cell Biol, 2019, 97( 3): 224－ 233. DOI: 10.1139/bcb－2018－0151.
[21]	KROLL T, PRESCHER M, SMITS S, et al. Structure and function of hepatobiliary ATP binding cassette transporters[J]. Chem Rev, 2021, 121( 9): 5240－ 5288. DOI: 10.1021/acs.chemrev.0c00659.
[22]	SAAD A BEN, BRUNEAU A, MAREUX E, et al. Molecular regulation of canalicular ABC transporters[J]. Int J Mol Sci, 2021, 22( 4): 2113. DOI: 10.3390/ijms22042113.
[23]	ZEIN AA, KAUR R, HUSSEIN T, et al. ABCG5/G8: a structural view to pathophysiology of the hepatobiliary cholesterol secretion[J]. Biochem Soc Trans, 2019, 47( 5): 1259－ 1268. DOI: 10.1042/BST20190130.
[24]	FARHAT D, REZAEI F, RISTOVSKI M, et al. Structural analysis of cholesterol binding and sterol selectivity by ABCG5/G8[J]. J Mol Biol, 2022, 434( 20): 167795. DOI: 10.1016/j.jmb.2022.167795.
[25]	PLUMMER AM, CULBERTSON AT, LIAO M. The ABCs of sterol transport[J]. Annu Rev Physiol, 2021, 83: 153－ 181. DOI: 10.1146/annurev－physiol－031620－094944.
[26]	LI R, LIU Y, SHI J, et al. Diosgenin regulates cholesterol metabolism in hypercholesterolemic rats by inhibiting NPC1L1 and enhancing ABCG5 and ABCG8[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2019, 1864( 8): 1124－ 1133. DOI: 10.1016/j.bbalip.2019.04.010.
[27]	CHEN J, HAN S, LI S, et al. Tandem mass tags quantitative proteome identification and function analysis of ABC transporters in neofusicoccum parvum[J]. Int J Mol Sci, 2022, 23( 17): 9908. DOI: 10.3390/ijms23179908.
[28]	LEE JY, KINCH LN, BOREK DM, et al. Crystal structure of the human sterol transporter ABCG5/ABCG8[J]. Nature, 2016, 533( 7604): 561－ 564. DOI: 10.1038/nature17666.
[29]	ZHANG PY, XU PY, SUN YB, et al. The cause of cholesterol gallstones from the perspective of molecular biology[J/CD]. Electr J Metabol Nutrit Cancer, 2022, 9( 4): 507－ 511. DOI: 10.16689/j.cnki.cn11－9349/r.2022.04.017. 张鹏云, 徐鹏远, 孙岩波, 等. 从分子生物学的角度来看胆固醇结石的成因[J]. 肿瘤代谢与营养电子杂志, 2022, 9( 4): 507－ 511. DOI: 10.16689/j.cnki.cn11－9349/r.2022.04.017.
[30]	WANG HH, PORTINCASA P, AFDHAL NH, et al. Lith genes and genetic analysis of cholesterol gallstone formation[J]. Gastroenterol Clin North Am, 2010, 39( 2): 185－ 207, vii－viii. DOI: 10.1016/j.gtc.2010.02.007.
[31]	KHANUJA B, CHEAH YC, HUNT M, et al. Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice[J]. Proc Natl Acad Sci U S A, 1995, 92( 17): 7729－ 7733. DOI: 10.1073/pnas.92.17.7729.
[32]	WANG DQ, AFDHAL NH. Genetic analysis of cholesterol gallstone formation: searching for Lith(gallstone) genes[J]. Curr Gastroenterol Rep, 2004, 6( 2): 140－ 150. DOI: 10.1007/s11894－004－0042－1.
[33]	WANG TY, PORTINCASA P, LIU M, et al. Mouse models of gallstone disease[J]. Curr Opin Gastroenterol, 2018, 34( 2): 59－ 70. DOI: 10.1097/MOG.0000000000000417.
[34]	BUCH S, SCHAFMAYER C, VÖLZKE H, et al. A genome－wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease[J]. Nat Genet, 2007, 39( 8): 995－ 999. DOI: 10.1038/ng2101.
[35]	GELLERT－KRISTENSEN H, DALILA N, FALLGAARD NIELSEN S, et al. Identification and replication of six loci associated with gallstone disease[J]. Hepatology, 2019, 70( 2): 597－ 609. DOI: 10.1002/hep.30313.
[36]	von KAMPEN O, BUCH S, NOTHNAGEL M, et al. Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus[J]. Hepatology, 2013, 57( 6): 2407－ 2417. DOI: 10.1002/hep.26009.
[37]	CHEN Y, WENG Z, LIU Q, et al. FMO3 and its metabolite TMAO contribute to the formation of gallstones[J]. Biochim Biophys Acta Mol Basis Dis, 2019, 1865( 10): 2576－ 2585. DOI: 10.1016/j.bbadis.2019.06.016.
[38]	BUSTOS BI, PÉREZ－PALMA E, BUCH S, et al. Variants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed latinos with mapuche native American ancestry[J]. Sci Rep, 2019, 9( 1): 772. DOI: 10.1038/s41598－018－35852－z.
[39]	CHEN Y, FAN XF, ZHENG ZQ, et al. Role of liver X receptor in process of cholesterol metabolism and its mechanism of action[J]. J Clin Hepatol, 2016, 32( 5): 1013－ 1017. DOI: 10.3969/j.issn.1001－5256.2016.05.049. 陈裕, 范晓飞, 郑忠清, 等. 肝X受体在胆固醇代谢过程中的作用机制[J]. 临床肝胆病杂志, 2016, 32( 5): 1013－ 1017. DOI: 10.3969/j.issn.1001－5256.2016.05.049.
[40]	UPPAL H, ZHAI Y, GANGOPADHYAY A, et al. Activation of liver X receptor sensitizes mice to gallbladder cholesterol crystallization[J]. Hepatology, 2008, 47( 4): 1331－ 1342. DOI: 10.1002/hep.22175.
[41]	WITTENBURG H, LYONS MA, LI R, et al. FXR and ABCG5/ABCG8 as determinants of cholesterol gallstone formation from quantitative trait locus mapping in mice[J]. Gastroenterology, 2003, 125( 3): 868－ 881. DOI: 10.1016/s0016－5085(03)01053－9.
[42]	FAN N, MENG K, ZHANG Y, et al. The effect of ursodeoxycholic acid on the relative expression of the lipid metabolism genes in mouse cholesterol gallstone models[J]. Lipids Health Dis, 2020, 19( 1): 158. DOI: 10.1186/s12944－020－01334－3.
[43]	CHENG S, ZOU M, LIU Q, et al. Activation of constitutive androstane receptor prevents cholesterol gallstone formation[J]. Am J Pathol, 2017, 187( 4): 808－ 818. DOI: 10.1016/j.ajpath.2016.12.013.
[44]	ZHAO F, MA S, ZHOU Y, et al. miRNA－223 suppresses mouse gallstone formation by targeting key transporters in hepatobiliary cholesterol secretion pathway[J]. Int J Biol Sci, 2021, 17( 15): 4459－ 4473. DOI: 10.7150/ijbs.65485.
[45]	SHEN L, HU C, ZHANG XL, et al. Research on effect of Shengqing Capsule on nuclear receptors and ATP binding cassette transporters in cholesterol gallstone mice[J]. Shanghai J Tradit Chin Med, 2021, 55( 8): 88－ 93. DOI: 10.16305/j.1007－1334.2021.2103068. 沈亮, 胡诚, 章学林, 等. 升清胶囊对胆固醇结石小鼠核受体及三磷酸腺苷结合盒(ABC)转运蛋白影响的研究[J]. 上海中医药杂志, 2021, 55( 8): 88－ 93. DOI: 10.16305/j.1007－1334.2021.2103068.
[46]	GAO Y, LIU C, LI J, et al. Efficacy of Lidan Tang on high－fat－diet induced hepatolithiasis in mice and possible mechanism[J]. J Tradit Chin Med, 2020, 40( 4): 584－ 592. DOI: 10.19852/j.cnki.jtcm.2020.04.007.
[47]	SONG XY, XU S, HU JF, et al. Piperine prevents cholesterol gallstones formation in mice[J]. Eur J Pharmacol, 2015, 751: 112－ 117. DOI: 10.1016/j.ejphar.2015.01.038.
[48]	CHEN G, WU S. Role of baicalin and liver X receptor alpha in the formation of cholesterol gallstones in mice[J]. Gastroenterol Res Pract, 2020, 2020: 1343969. DOI: 10.1155/2020/1343969.
[49]	ZHUANG Q, CHENG J, XIA J, et al. Gypenosides prevent and dissolve cholesterol gallstones by modulating the homeostasis of cholesterol and bile acids[J]. Front Med(Lausanne), 2022, 9: 818144. DOI: 10.3389/fmed.2022.818144.