脂质代谢中的重要靶点：法尼酯X受体（FXR）

doi:10.12092/j.issn.1009-2501.2018.08.020

中国临床药理学与治疗学 ›› 2018, Vol. 23 ›› Issue (8): 955-960.doi: 10.12092/j.issn.1009-2501.2018.08.020

• 综述与讲座 • 上一篇

脂质代谢中的重要靶点：法尼酯X受体（FXR）

刘晓红¹，李玲¹，齐振华¹，陈彬尧¹，赵慧佳¹，郝卓文¹，乐江²，叶啟发^1,3，吴建国⁴

¹武汉大学中南医院，武汉大学肝胆疾病研究院，武汉大学移植医学中心，移植医学技术湖北省重点实验室，武汉 430071，湖北；²武汉大学基础医学院药理教研室，武汉 430071，湖北； ³中南大学湘雅三医院，卫生部移植医学工程技术研究中心，长沙 410013，湖南； ⁴武汉大学生命科学学院，病毒学国家重点实验室，武汉 430071，湖北

收稿日期:2018-04-04 修回日期:2018-05-23 出版日期:2018-08-26 发布日期:2018-08-28
通讯作者: 叶啟发，男，博士，教授，主任医师，研究方向：肝胆外科，器官移植。 Tel: 027-67812988 E-mail: yqf_china@163.com
作者简介:刘晓红，女，本科，研究方向：移植术后代谢性疾病的病理机制。 Tel: 13297991056 E-mail: 13297991056@163.com
基金资助:
2016年湖北省技术创新专项（2016ACA155）；病毒学国家重点实验室开放研究基金资助项目（2018KF005）

Farnesoid X receptor is an important target in lipid metabolism

LIU Xiaohong ¹, LI Ling¹, QI Zhenhua ¹, CHEN Binyao¹, ZHAO Huijia¹, HAO Zhuowen¹, YUE Jiang², YE Qifa ^1,3，WU Jianguo⁴

¹Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan 430071, Hubei, China；²Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, Hubei, China; ³The 3rd Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, Changsha 410013, Hunan, China; ⁴College of Life Sciences of Wuhan University, State Key Laboratory of Virology, Wuhan 430071, Hubei, China

Received:2018-04-04 Revised:2018-05-23 Online:2018-08-26 Published:2018-08-28

摘要/Abstract

摘要：

法尼酯X受体（FXR）是一种可以被胆汁酸激活的核受体，通过调控CYP7A1等靶基因的表达，影响脂质在肝脏、小肠等重要器官的各种代谢过程。本文拟就近几年来探究FXR在脂质合成、氧化、吸收及转运环节中的作用机制作一综述，进而FXR有望成为治疗脂肪肝、高甘油三酯血症等疾病的药物靶点，为预防和治疗临床上疾病的发生提供科学依据。

关键词: 法尼酯X受体, 脂质合成, 脂质氧化, 脂质吸收

Abstract:

Farnesoid X receptor (FXR) is a kind of nuclear receptors of bile acid activation. FXR influences lipid in the liver, small intestine, and other important organs of various metabolic processes through regulating the expression of target genes such as CYP7A1. This review focuses on the influence of FXR in lipid metabolism on the basis of the related research reviews in recent years, and hopes to provide a scientific basis for prevention and treatment of clinical diseases as FXR is becoming the expected drug-target for diseases such as fatty liver, high blood triglycerides, etc.

Key words: FXR, lipid synthesis, lipid oxidation, lipid absorption

中图分类号:

R589.2

刘晓红，李玲，齐振华，陈彬尧，赵慧佳，郝卓文，乐江，叶啟发，吴建国. 脂质代谢中的重要靶点：法尼酯X受体（FXR）[J]. 中国临床药理学与治疗学, 2018, 23(8): 955-960.

LIU Xiaohong, LI Ling, QI Zhenhua, CHEN Binyao, ZHAO Huijia, HAO Zhuowen, YUE Jiang, YE Qifa，WU Jianguo. Farnesoid X receptor is an important target in lipid metabolism[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(8): 955-960.

参考文献

［1］Cave MC, Clair HB, Hardesty JE, et al. Nuclear receptors and nonalcoholic fatty liver disease［J］. Biochim Biophys Acta, 2016, 1859(9): 1083-1099.
［2］Thompson MD, Moghe A, Cornuet P, et al. β-catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis ［J］. Hepatology, 2018, 67(3): 955-971.
［3］Evans RM, Mangelsdorf DJ. Nuclear receptors, RXR, and the big bang ［J］. Cell, 2014, 157(1): 255-266.
［4］Forman BM, Goode E, Chen J, et al. Identification of a nuclear receptor that is activated by farnesol metabolites ［J］. Cell, 1995, 81(5): 687-693.
［5］Yuan ZQ, Li KW. Role of farnesoid X receptor in cholestasis ［J］. J Dig Dis, 2016, 17(8): 501-509.
［6］Pellicciari R, Costantino G, Fiorucci S, et al. Farnesoid X receptor:from structure to potential clinical applications ［J］. J Med Chem, 2005, 48(17): 5383-5403.
［7］Makishima M, Okamoto AY, Repa J J, et al. Identification of a nuclear receptor for bile acids ［J］. Science, 1999, 284(5418): 1362 -1365.
［8］徐千，李玲，魏婉慧，等. 法尼酯衍生物X受体基因多态性与代谢性疾病的相关性［J］. 中国临床药理学与治疗学，2017, 10(1): 1180-1188.
［9］Moon YA. The SCAP/SREBP pathway: a mediator of hepatic steatosis［J］. Endocrinol Metab (Seoul), 2017, 32(1): 6-10.
［10］DeBose-Boyd RA, Ye J. SREBPs in lipid metabolism, insulin signaling, and beyond ［J］. Trends Biochem Sci, 2018, 43(5): 358-368.
［11］Chávez-Talavera O, Tailleux A, Lefebvre P, et al. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease ［J］. Gastroenterology, 2017, 152(7): 1679-1694.
［12］Yang Z, Tsuchiya H, Zhang Y, et al. REV-ERBα activates C/EBP homologous protein to control small heterodimer partner-mediated oscillation of alcoholic fatty liver［J］. Am J Pathol, 2016, 186(11): 2909-2920.
［13］Gai Z, Gui T, Hiller C, et al. Farnesoid x receptor protects against kidney injury in uninephrectomized obese mice ［J］. J Biol Chem, 2016, 291(5): 2397-2411.
［14］Levi M. Role of Bile Acid regulated nuclear receptor FXR and G protein coupled receptor TGR5 in regulation of cardiorenal syndrome［J］. Hypertension, 2016, 67(6): 1080-1084.
［15］D'Agati VD, Chagnac A, de Vries AP, et al. Obesity-related glomerulopathy clinical and pathologic characteristics and pathogenesis［J］. Nat Rev Nephrol, 2016, 12(8): 453-471.
［16］Hashidume T, Kato A, Tanaka T, et al. Single ingestion of soy β-conglycinin induces increased postprandial circulating FGF21 levels exerting beneficial health effects ［J］. Sci Rep, 2016, 6(1): 28183.
［17］Dwivedi SK, Singh N, Kumari R, et al. Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α［J］. Mol Endocrinol, 2011, 25(6): 922-932.
［18］Preidis GA, Kim KH, Moore DD. Nutrient-sensing nuclear receptors PPARα and FXR control liver energy balance ［J］. J Clin Invest, 2017, 127(4): 1193-1201.
［19］Pathak P, Liu H, Boehme S, et al. Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism［J］. J Biol Chem, 2017, 292(26): 11055-11069.
［20］Liu HM, Lee TY, Liao JF. GW4064 attenuates lipopolysaccharide induced hepatic inflammation and apoptosis through inhibition of the Toll like receptor 4 mediated p38 mitogen activated protein kinase signaling pathway in mice［J］. Int J Mol Med, 2018, 41(3): 1455-1462.
［21］ Kim KH, Choi S, Zhou Y, et al. Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice［J］. Hepatology, 2017, 66(2): 498-509.
［22］Degirolamo C, Modica S, Vacca M, et al. Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation［J］. Hepatology, 2015, 61(1): 161-170.
［23］Guo C, LaCerte C, Edwards JE, et al. Farnesoid x receptor agonists obeticholic acid and chenodeoxycholic acid increase bile acid efflux in sandwich-cultured human hepatocytes: functional evidence and mechanisms ［J］. J Pharmacol Exp Ther, 2018, 365(2): 413-421.
［24］Gonzalez FJ, Jiang C, Patterson AD. An intestinal microbiota-farnesoid x receptor axis modulates metabolic disease［J］. Gastroenterology, 2016, 151(5): 845-859.
［25］Kazgan N, Metukuri MR, Purushotham A, et al. Intestine-specific deletion of sirt1 in mice impairs DCoH2-HNF1α-FXR signaling and alters systemic bile acid homeostasis［J］. Gastroenterology, 2014, 146(4): 1006-1016.
［26］Fang S, Suh JM, Reilly SM, et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulinresistance ［J］. Nat Med, 2015, 21(2): 159-165.
［27］Mazuy C, Helleboid A, Staels B, et al. Nuclear bile acid signaling through the farnesoid X receptor［J］. Cell Mol Life Sci, 2015, 72(9): 1631-1650.
［28］Aguiar Vallim TQ, Tarling EJ, Edwards PA, et al. Pleiotropic roles of bile acids in metabolism［J］. Cell metabolism, 2013, 17: 657-669.
［29］Xu Y, Li F, Zalzala M, et al. FXR activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption ［J］. Hepatology, 2016, 64(4): 1072-1085.
［30］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 FGF15 signal ［J］. Liver Int. 2015, 35(4): 1133-1144.
［31］Teodoro JS, Rolo AP, Palmeira CM. Hepatic FXR: key regulator of whole-body energy metabolism ［J］. Trends Endocrinol Metab, 2011, 22(11): 458-466.
［32］Schumacher JD, Kong B, Pan Y, et al. The effect of fibroblast growth factor 15 deficiency on the development of high fat diet induced non-alcoholic steatohepatitis ［J］. Toxicol Appl Pharmacol, 2017, 330: 1-8.
［33］Carino A, Cipriani S, Marchianò S, et al. Gpbar1 agonism promotes a Pgc-1α-dependent browning of white adipose tissue and energy expenditure and reverses diet-induced steatohepatitis in mice［J］. Sci Rep, 2017, 7(1): 13689.
［34］杨帅. 沉默调节蛋白1在非酒精性脂肪性肝病发生发展中的作用［J］. 临床肝胆病杂志, 2018, 3(1): 649-652.
［35］Engin A. Non-alcoholic fatty liver disease［J］. Adv Exp Med Biol, 2017, 960: 443-467.
［36］Neusch W, Tetri BA, Loomba R, et al. Farnesoid X nuclear receptor ligand obeticholic acid for noncirrhotic, non alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial ［J］. Lancet, 2015, 385(9972): 956-965.

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脂质代谢中的重要靶点：法尼酯X受体（FXR）

Farnesoid X receptor is an important target in lipid metabolism

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