胆汁酸代谢及其受体在非酒精性脂肪性肝病发生发展中的作用

张阳; 李军祥; 王允亮

doi:10.3969/j.issn.1001-5256.2020.06.040

胆汁酸代谢及其受体在非酒精性脂肪性肝病发生发展中的作用

DOI: 10.3969/j.issn.1001-5256.2020.06.040

1. 北京中医药大学研究生院
2. 北京中医药大学东方医院消化内科

基金项目:

国家自然科学基金青年课题(81503407)；北京中医药大学科研创新岐黄团队项目(2019-JYB-TD004);北京中医药大学基本科研业务费项目(2019-JYB-JS-134)；

详细信息

中图分类号: R575.5
计量
- 文章访问数: 679
- HTML全文浏览量: 30
- PDF下载量: 143
- 被引次数: 0
出版历程
- 收稿日期: 2020-01-08
- 出版日期: 2020-06-20

Role of bile acid metabolism and related receptors in the development and progression of nonalcoholic fatty liver disease

Graduated School of Beijing University of Chinese Medicine
Department of Gastroenterology,Dongfang Hospital,Beijing University of Chinese Medicine

Research funding:

摘要

摘要:
肠肝循环在非酒精性脂肪性肝病发病机制中扮演重要角色。胆汁酸作为肠肝循环的基础物质,在机体脂质代谢、肠道菌群调节、宿主免疫等方面发挥重要作用。总结了胆汁酸作为信号分子,激活肝、肠等组织中的胆汁酸受体,如法尼醇X受体、G蛋白偶联受体5、孕烷X受体和维生素D受体等,参与非酒精性脂肪性肝病发病机制的研究进展。认为针对以上靶点进行研究,有望研发治疗非酒精性脂肪性肝病的有效药物,但尚待进一步探索。
- 非酒精性脂肪性肝病 /
- 胆酸类 /
- 肠肝循环
Abstract:
Enterohepatic circulation plays an important role in the pathogenesis of nonalcoholic fatty liver disease( NAFLD). Bile acid is the basic substance of enterohepatic circulation and plays an important role in lipid metabolism,intestinal flora regulation,and host immunity. This article summarizes the research advances in bile acid which acts as a signal molecule to activate bile acid receptors in the liver and intestine,such as farnesoid X receptor,G protein-coupled receptor 5,pregnane X receptor,and vitamin D receptor,and is thus involved in the pathogenesis of NAFLD. It is expected to develop effective drugs for the treatment of NALFD based on the above targets,but there is still a need for further exploration.
- non-alcoholic fatty liver disease /
- cholic acids /
- enterohepatic circulation

HTML全文

参考文献(45)

[1] ZHOU F,ZHOU J,WANG W,et al. Unexpected rapid increase in the burden of NAFLD in China from 2008 to 2018:A systematic review and meta-analysis[J]. Hepatology,2019,70(4):1119-1133.

[2] SLIJEPCEVIC D,van de GRAAF SF. Bile acid uptake transporters as targets for therapy[J]. Dig Dis,2017,35(3):251-258.

[3] YANG ZX,SHEN W,SUN H. Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease[J]. Hepatol Int,2010,4(4):741-748.

[4] BECHMANN LP,KOCABAYOGLU P,SOWA JP,et al. Free fatty acids repress small heterodimer partner(SHP)activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis[J].Hepatology,2013,57(4):1394-1406.

[5] PURI P,DAITA K,JOYCE A,et al. The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids[J]. Hepatology,2018,67(2):534-548.

[6] TANG Y,ZHANG J,LI J,et al. Turnover of bile acids in liver,serum and caecal content by high-fat diet feeding affects hepatic steatosis in rats[J]. Biochim Biophys Acta Mol Cell Biol Lipids,2019,1864(10):1293-1304.

[7] SUGA T,YAMAGUCHI H,OGURA J,et al. Altered bile acid composition and disposition in a mouse model of non-alcoholic steatohepatitis[J]. Toxicol Appl Pharmacol,2019,379:114664.

[8] ARAB JP,KARPEN SJ,DAWSON PA,et al. Bile acids and nonalcoholic fatty liver disease:Molecular insights and therapeutic perspectives[J]. Hepatology,2017,65(1):350-362.

[9] PREIDIS GA,KIM KH,MOORE DD. Nutrient-sensing nuclear receptors PPARαand FXR control liver energy balance[J]. J Clin Invest,2017,127(4):1193-1201.

[10] VELAZQEZ-VILLEGAS LA,PERINO A,LEMOS V,et al. TGR5signalling promotes mitochondrial fission and beige remodelling of white adipose tissue[J]. Nat Commun,2018,9(1):245.

[11] CHA BH,KIM JS,AHN JC,et al. The role of tauroursodeoxycholic acid on adipogenesis of human adipose-derived stem cells by modulation of ER stress[J]. Biomaterials,2014,35(9):2851-2858.

[12] Human Microbiome Project Consortium. Structure,function and diversity of the healthy human microbiome[J]. Nature,2012,486(7402):207-214.

[13] BRANDL K,SCHNABL B. Intestinal microbiota and nonalcoholic steatohepatitis[J]. Curr Opin Gastroenterol,2017,33(3):128-133.

[14] KOLODZIEJCZYK AA,ZHENG D,SHIBOLET O,et al. The role of the microbiome in NAFLD and NASH[J]. EMBO Mol Med,2019,11(2):e9302.

[15] SAFARI Z,GRARD P. The links between the gut microbiome and non-alcoholic fatty liver disease(NAFLD)[J]. Cell Mol Life Sci,2019,76(8):1541-1558.

[16] WAHLSTRM A,KOVATCHEVA-DATCHARY P,STHLMAN M,et al. Crosstalk between bile acids and gut microbiota and its impact on farnesoid X receptor signalling[J]. Dig Dis,2017,35(3):246-250.

[17] WAHLSTRM A,SAYIN SI,MARSCHALL HU,et al. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism[J]. Cell Metab,2016,24(1):41-50.

[18] CHENG S,ZHU L,FADEN HS. Interactions of bile acids and the gut microbiota:Learning from the differences in Clostridium difficile infection between children and adults[J]. Physiol Genomics,2019,51(6):218-223.

[19] FOUTS DE,TORRALBA M,NELSON KE,et al. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease[J]. J Hepatol,2012,56(6):1283-1292.

[20] DEVKOTA S,WANG Y,MUSCH MW,et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10–/–mice[J]. Nature,2012,487(7405):104-108.

[21] SUTTI S,BRUZZS,ALBANO E. The role of immune mechanisms in alcoholic and nonalcoholic steatohepatitis:A 2015 update[J].Expert Rev Gastroenterol Hepatol,2016,10(2):243-253.

[22] FIORUCCI S,BIAGIOLI M,ZAMPELLA A,et al. Bile acids activated receptors regulate innate immunity[J]. Front Immunol,2018,9:1853.

[23] BIAGIOLI M,CARINO A. Signaling from intestine to the host:How bile acids regulate intestinal and liver immunity[J].Handb Exp Pharmacol,2019,256:95-108.

[24] FEROLLA SM,ARMILIATO GN,COUTO CA,et al. The role of intestinal bacteria overgrowth in obesity-related nonalcoholic fatty liver disease[J]. Nutrients,2014,6(12):5583-5599.

[25] 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):802-816.

[26] RENGA B,MENCARELLI A,CIPRIANI S,et al. The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation[J]. PLo S One,2013,8(1):e54472.

[27] 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.

[28] JIANG C,XIE C,LI F,et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease[J]. J Clin Invest,2015,125(1):386-402.

[29] SAMUEL VT,SHULMAN GI. Mechanisms for insulin resistance:Common threads and missing links[J]. Cel,2012,148(5):852-871.

[30] CONTRERAS C,GONZLEZ-GARCA I,MARTNEZ-SNCHEZ N,et al. Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance[J]. Cell Rep,2014,9(1):366-377.

[31] FANG S,SUH JM,REILLY SM,et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance[J]. Nat Med,2015,21(2):159-165.

[32] SCHMITT J,KONG B,STIEGER B,et al. Protective effects of farnesoid X receptor(FXR)on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15signal[J]. Liver Int,2015,35(4):1133-1144.

[33] LEE EA,LEE DI,KIM HY,et al. Cyp7a1 is continuously increased with disrupted Fxr-mediated feedback inhibition in hypercholesterolemic TALLYHO/Jng mice[J]. Biochem Biophys Acta Mol Cell Biol Lipids,2018,1863(1):20-25.

[34] NEUSCHWANDER-TETRI BA,LOOMBA R,SANYAL AJ,et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic,non-alcoholic steatohepatitis(FLINT):A multicentre,randomised,placebo-controlled trial[J]. Lancet,2015,385(9972):956-965.

[35] VASSILEVA G,HU W,HOOS L,et al. Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice[J]. J Endocrinol,2010,205(3):225-232.

[36] McMAHAN RH,WANG XX,CHENG LL,et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease[J]. J Biol Chem,2013,288(17):11761-11770.

[37] THOMAS C,GIOIELLO A,NORIEGA L,et al. TGR5-mediated bile acid sensing controls glucose homeostasis[J]. Cell Metab,2009,10(3):167-177.

[38] CHAI SC,CHERIAN MT,WANG YM,et al. Small-molecule modulators of PXR and CAR[J]. Biochim Biophys Acta,2016,1859(9):1141-1154.

[39] COPPLE BL,LI T. Pharmacology of bile acid receptors:Evolution of bile acids from simple detergents to complex signaling molecules[J]. Pharmacol Res,2016,104:9-21.

[40] STAUDINGER JL,GOODWIN B,JONES SA,et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity[J]. Proc Natl Acad Sci U S A,2001,98(6):3369-3374.

[41] LI X,WANG Z,KLAUNIG JE. Modulation of xenobiotic nuclear receptors in high-fat diet induced non-alcoholic fatty liver disease[J]. Toxicology,2018,410:199-213.

[42] ZHANG X,MA Z,LIANG Q,et al. Tanshinone IIA exerts protective effects in a LCA-induced cholestatic liver model associated with participation of pregnane X receptor[J]. J Ethnopharmacol,2015,164:357-367.

[43] CHENG J,FANG ZZ,KIM JH,et al. Intestinal CYP3A4 protects against lithocholic acid-induced hepatotoxicity in intestine-specific VDR-deficient mice[J]. J Lipid Res,2014,55(3):455-465.

[44] DELLA CORTE C,CARPINO G,de VITO R,et al. Docosahexanoic acid plus vitamin D treatment improves features of NAFLD in children with serum vitamin D deficiency:Results from a single centre trial[J]. PLo S One,2016,11(12):e0168216.

[45] LORVAND AMIRI H,AGAH S,TOLOUEI AZAR J,et al. Effect of daily calcitriol supplementation with and without calcium on disease regression in non-alcoholic fatty liver patients following an energy-restricted diet:Randomized, controlled,double-blind trial[J]. Clin Nutr,2017,36(6):1490-1497.

施引文献

资源附件(0)

访问统计