顶端钠依赖性胆汁酸转运蛋白（ASBT）在肝胆疾病中的作用

谢晓暄; 杜丽娜; 郭紫云; 杨燕

doi:10.12449/JCH240133

顶端钠依赖性胆汁酸转运蛋白（ASBT）在肝胆疾病中的作用

DOI: 10.12449/JCH240133

国家儿童医学中心，首都医科大学附属北京儿童医院中医科，北京 100045

基金项目:

国家自然科学基金 (82205184);

北京市属医院科研培育计划 (PZ2022027)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：谢晓暄负责文献检索及文章撰写；杜丽娜负责文章修改；郭紫云负责文献检索；杨燕负责指导及校正。

详细信息

通信作者:
杨燕， yy2303@sina.com （ORCID： 0000-0003-1070-9614）

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出版历程
- 收稿日期: 2023-03-29
- 录用日期: 2023-05-06
- 出版日期: 2024-01-23

Role of apical sodium-dependent bile acid transporter in hepatobiliary diseases

Department of Traditional Chinese Medicine，National Center for Children’s Health，Beijing Children’s Hospital，Capital Medical University，Beijing 100045，China

Research funding:

National Natural Science Foundation of China (82205184);

Bejing Municipal Administration of Hospital Incubating Program (PZ2022027)

More Information

Corresponding author: YANG yan， yy2303@sina.com （ORCID： 0000-0003-1070-9614）

摘要

摘要: 顶端钠依赖性胆汁酸转运蛋白（ASBT）是负责胆汁酸肠道重吸收的关键转运体，对维持胆汁酸和胆固醇稳态起重要作用，其表达受到转录因子、核受体和肠道微生物等多种因素的调控。ASBT的表达和功能异常会导致胆汁酸及胆固醇代谢紊乱，引起多种肝胆相关疾病。目前，ASBT作为一种治疗靶点已受到广泛关注。本文阐述了ASBT的生物学特征及表达调控机制，并对ASBT在肝胆疾病中的作用进行了综述，为相关疾病的治疗提供新方向。
- 顶端钠依赖性胆汁酸转运蛋白 /
- 胆汁酸类 /
- 胆汁淤积
Abstract: Apical sodium-dependent bile acid transporter （ASBT） is a key transporter responsible for intestinal reabsorption of bile acid and plays an important role in maintaining bile acid and cholesterol homeostasis， and its expression is regulated by various factors including transcription factors， nuclear receptors， and intestinal microflora. The abnormal expression and function of ASBT can lead to disorders in the metabolism of bile acid and cholesterol， causing a variety of hepatobiliary diseases. At present， ASBT has attracted wide attention as a therapeutic target. This article elaborates on the biological characteristics and expression regulation mechanism of ASBT and reviews the role of ASBT in hepatobiliary diseases， in order to provide a new direction for the treatment of related diseases.
- Apical Sodium Dependent Bile Acid Transporter /
- Bile Acid /
- Cholestasis

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参考文献(39)

[1]	XIAO L, PAN GY. 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.
[2]	LUO ZL, CHENG L, WANG T, et al. Bile acid transporters are expressed and heterogeneously distributed in rat bile ducts[J]. Gut Liver, 2019, 13( 5): 569- 575. DOI: 10.5009/gnl18265.
[3]	LI M, WANG Q, LI Y, et al. Apical sodium-dependent bile acid transporter, drug target for bile acid related diseases and delivery target for prodrugs: Current and future challenges[J]. Pharmacol Ther, 2020, 212: 107539. DOI: 10.1016/j.pharmthera.2020.107539.
[4]	LI J, ZHENG KY, ZHANG BB. Mechanism of action of bile acid metabolism in regulating cholestatic liver disease and the research and development of drugs[J]. J Clin Hepatol, 2021, 37( 10): 2482- 2487. DOI: 10.3969/j.issn.1001-5256.2021.10.048. 李静, 郑葵阳, 张蓓蓓. 胆汁酸代谢调节胆汁淤积性肝病的作用机制及药物研发[J]. 临床肝胆病杂志, 2021, 37( 10): 2482- 2487. DOI: 10.3969/j.issn.1001-5256.2021.10.048.
[5]	WANG XD, LYU Y, JI YJ, et al. An engineered disulfide bridge traps and validates an outward-facing conformation in a bile acid transporter[J]. Acta Crystallogr D Struct Biol, 2021, 77( Pt 1): 108- 116. DOI: 10.1107/S205979832001517X.
[6]	KAZGAN N, METUKURI MR, PURUSHOTHAM A, et al. Intestine-specific deletion of SIRT1 in mice impairs DCoH2-HNF-1α-FXR signaling and alters systemic bile acid homeostasis[J]. Gastroenterology, 2014, 146( 4): 1006- 1016. DOI: 10.1053/j.gastro.2013.12.029.
[7]	LIU S, LIU M, ZHANG ML, et al. Transcription factor Klf9 controls bile acid reabsorption and enterohepatic circulation in mice via promoting intestinal Asbt expression[J]. Acta Pharmacol Sin, 2022, 43( 9): 2362- 2372. DOI: 10.1038/s41401-021-00850-x.
[8]	MA L, JÜTTNER M, KULLAK-UBLICK GA, et al. Regulation of the gene encoding the intestinal bile acid transporter ASBT by the caudal-type homeobox proteins CDX1 and CDX2[J]. Am J Physiol Gastrointest Liver Physiol, 2012, 302( 1): G123- G133. DOI: 10.1152/ajpgi.00102.2011.
[9]	YANG N, DONG YQ, JIA GX, et al. ASBT(SLC10A2): A promising target for treatment of diseases and drug discovery[J]. Biomed Pharmacother, 2020, 132: 110835. DOI: 10.1016/j.biopha.2020.110835.
[10]	NGUYEN JT, RIESSEN R, ZHANG TY, et al. Deletion of intestinal SHP impairs short-term response to cholic acid challenge in male mice[J]. Endocrinology, 2021, 162( 8): bqab063. DOI: 10.1210/endocr/bqab063.
[11]	SONNE DP. Mechanisms in endocrinology: FXR signalling: A novel target in metabolic diseases[J]. Eur J Endocrinol, 2021, 184( 5): R193- R205. DOI: 10.1530/EJE-20-1410.
[12]	OUT C, PATANKAR JV, DOKTOROVA M, et al. Gut microbiota inhibit Asbt-dependent intestinal bile acid reabsorption via Gata4[J]. J Hepatol, 2015, 63( 3): 697- 704. DOI: 10.1016/j.jhep.2015.04.030.
[13]	CHAUDHARI SN, LUO JN, HARRIS DA, et al. A microbial metabolite remodels the gut-liver axis following bariatric surgery[J]. Cell Host Microbe, 2021, 29( 3): 408- 424. e 7. DOI: 10.1016/j.chom.2020.12.004.
[14]	HASSAN S, HERTEL P. Overview of progressive familial intrahepatic cholestasis[J]. Clin Liver Dis, 2022, 26( 3): 371- 390. DOI: 10.1016/j.cld.2022.03.003.
[15]	van der MARK VA, de WAART DR, HO-MOK KS, et al. The lipid flippase heterodimer ATP8B1-CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter(SLC10A2/ASBT) in intestinal Caco-2 cells[J]. Biochim Biophys Acta, 2014, 1842( 12 Pt A): 2378- 2386. DOI: 10.1016/j.bbadis.2014.09.003.
[16]	THOMPSON RJ, ARNELL H, ARTAN R, et al. Odevixibat treatment in progressive familial intrahepatic cholestasis: A randomised, placebo-controlled, phase 3 trial[J]. Lancet Gastroenterol Hepatol, 2022, 7( 9): 830- 842. DOI: 10.1016/S2468-1253(22)00093-0.
[17]	SHIRLEY M. Maralixibat: First approval[J]. Drugs, 2022, 82( 1): 71- 76. DOI: 10.1007/s40265-021-01649-0.
[18]	KAMATH BM, GOLDSTEIN A, HOWARD R, et al. Maralixibat treatment response in alagille syndrome is associated with improved health-related quality of life[J]. J Pediatr, 2023, 252: 68- 75.e5. DOI: 10.1016/j.jpeds.2022.09.001.
[19]	KUNST RF, de WAART DR, WOLTERS F, et al. Systemic ASBT inactivation protects against liver damage in obstructive cholestasis in mice[J]. JHEP Rep, 2022, 4( 11): 100573. DOI: 10.1016/j.jhepr.2022.100573.
[20]	CABALLERO-CAMINO FJ, RODRIGUES PM, WÅNGSELL F, et al. A3907, a systemic ASBT inhibitor, improves cholestasis in mice by multiorgan activity and shows translational relevance to humans[J]. Hepatology, 2023. DOI: 10.1097/HEP.0000000000000376.[ Online ahead of print]
[21]	ZHOU L, WANG XT, SONG FL, et al. Effect of Huayu Lidan decoction combined with a comprehensive intervention in the treatment of patients with intrahepatic cholestasis of pregnancy[J]. J Changchun Univ Chin Med, 2022, 38( 11): 1234- 1237. DOI: 10.13463/j.cnki.cczyy.2022.11.014. 周璐, 王希涛, 宋风丽, 等. 化瘀利胆汤结合综合干预治疗妊娠期肝内胆汁淤积症[J]. 长春中医药大学学报, 2022, 38( 11): 1234- 1237. DOI: 10.13463/j.cnki.cczyy.2022.11.014.
[22]	WANG LR, LIU J. Role of miR-221/222 and its target genes in the pathogenesis of intrahepatic cholestasis of pregnancy[J]. J Chongqing Med Univ, 2019, 44( 5): 662- 667. DOI: 10.13406/j.cnki.cyxb.001937. 王林若, 刘建. miR-221/222及其靶基因在妊娠期肝内胆汁淤积症发病机制中作用的研究[J]. 重庆医科大学学报, 2019, 44( 5): 662- 667. DOI: 10.13406/j.cnki.cyxb.001937.
[23]	ONTSOUKA E, EPSTEIN A, KALLOL S, et al. Placental expression of bile acid transporters in intrahepatic cholestasis of pregnancy[J]. Int J Mol Sci, 2021, 22( 19): 10434. DOI: 10.3390/ijms221910434.
[24]	OVADIA C, PERDONES-MONTERO A, SPAGOU K, et al. Enhanced microbial bile acid deconjugation and impaired ileal uptake in pregnancy repress intestinal regulation of bile acid synthesis[J]. Hepatology, 2019, 70( 1): 276- 293. DOI: 10.1002/hep.30661.
[25]	MEADOWS V, MARAKOVITS C, EKSER B, et al. Loss of apical sodium bile acid transporter alters bile acid circulation and reduces biliary damage in cholangitis[J]. Am J Physiol Gastrointest Liver Physiol, 2023, 324( 1): G60- G77. DOI: 10.1152/ajpgi.00112.2022.
[26]	MIETHKE AG, ZHANG WJ, SIMMONS J, et al. Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice[J]. Hepatology, 2016, 63( 2): 512- 523. DOI: 10.1002/hep.27973.
[27]	GAO LX, WANG L, WOO E, et al. Clinical management of primary biliary cholangitis-strategies and evolving trends[J]. Clin Rev Allergy Immunol, 2020, 59( 2): 175- 194. DOI: 10.1007/s12016-019-08772-7.
[28]	AL-DURY S, WAHLSTRÖM A, WAHLIN S, et al. Pilot study with IBAT inhibitor A4250 for the treatment of cholestatic pruritus in primary biliary cholangitis[J]. Sci Rep, 2018, 8( 1): 6658. DOI: 10.1038/s41598-018-25214-0.
[29]	CHENG SH, ZOU M, LIU QH, 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.
[30]	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.
[31]	WANG CE, XU WT, GONG J, et al. Research progress in the treatment of nonalcoholic fatty liver disease[J]. Chin J Med Offic, 2022, 50( 9): 897- 899, 903. DOI: 10.16680/j.1671-3826.2022.09.06. 王彩娥, 许文涛, 宫建, 等. 非酒精性脂肪性肝病治疗研究进展[J]. 临床军医杂志, 2022, 50( 9): 897- 899, 903. DOI: 10.16680/j.1671-3826.2022.09.06.
[32]	GILLARD J, CLERBAUX LA, NACHIT M, et al. Bile acids contribute to the development of non-alcoholic steatohepatitis in mice[J]. JHEP Rep, 2021, 4( 1): 100387. DOI: 10.1016/j.jhepr.2021.100387.
[33]	van de PEPPEL IP, BERTOLINI A, van DIJK TH, et al. Efficient reabsorption of transintestinally excreted cholesterol is a strong determinant for cholesterol disposal in mice[J]. J Lipid Res, 2019, 60( 9): 1562- 1572. DOI: 10.1194/jlr.M094607.
[34]	SALIC K, KLEEMANN R, WILKINS-PORT C, et al. Apical sodium-dependent bile acid transporter inhibition with volixibat improves metabolic aspects and components of non-alcoholic steatohepatitis in Ldlr^-/-. Leiden mice[J]. PLoS One, 2019, 14( 6): e0218459. DOI: 10.1371/journal.pone.0218459.
[35]	van de PEPPEL IP, RAO A, DOMMERHOLT MB, et al. The beneficial effects of apical sodium-dependent bile acid transporter inactivation depend on dietary fat composition[J]. Mol Nutr Food Res, 2020, 64( 24): e2000750. DOI: 10.1002/mnfr.202000750.
[36]	RAO A, van de PEPPEL IP, GUMBER S, et al. Attenuation of the hepatoprotective effects of ileal apical sodium dependent bile acid transporter(ASBT) inhibition in choline-deficient L-amino acid-defined(CDAA) diet-fed mice[J]. Front Med, 2020, 7: 60. DOI: 10.3389/fmed.2020.00060.
[37]	MATYE DJ, WANG HW, LUO WY, et al. Combined ASBT inhibitor and FGF15 treatment improves therapeutic efficacy in experimental nonalcoholic steatohepatitis[J]. Cell Mol Gastroenterol Hepatol, 2021, 12( 3): 1001- 1019. DOI: 10.1016/j.jcmgh.2021.04.013.
[38]	LIU YL, LIU T, ZHAO X, et al. New insights into the bile acid-based regulatory mechanisms and therapeutic perspectives in alcohol-related liver disease[J]. Cell Mol Life Sci, 2022, 79( 9): 486. DOI: 10.1007/s00018-022-04509-6.
[39]	MATYE DJ, LI Y, CHEN C, et al. Gut-restricted apical sodium-dependent bile acid transporter inhibitor attenuates alcohol-induced liver steatosis and injury in mice[J]. Alcohol Clin Exp Res, 2021, 45( 6): 1188- 1199. DOI: 10.1111/acer.14619.