肠道法尼醇X受体在非酒精性脂肪性肝病中的作用机制及相关靶向药物

张凯玲; 李良平

doi:10.3969/j.issn.1001-5256.2020.05.047

肠道法尼醇X受体在非酒精性脂肪性肝病中的作用机制及相关靶向药物

DOI: 10.3969/j.issn.1001-5256.2020.05.047

四川省医学科学院四川省人民医院消化内科

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中图分类号: R575.5
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出版历程
- 出版日期: 2020-05-20

Mechanism of action of intestinal farnesoid X receptor in nonalcoholic fatty liver disease and related targeted drugs

Department of Gastroenterology, Sichuan Provincial People’s Hospital, Sichuan Academy of Medical Sciences, Chengdu 610072, China

摘要

摘要:
近年来非酒精性脂肪性肝病(NAFLD)发病率日益剧增,若患者不良生活方式无法及时调整,且临床尚缺乏有效的药物,使得NAFLD的治疗差强人意。法尼醇X受体(FXR)作为胆汁酸的主要受体,通过参与糖、脂代谢来影响NAFLD,而肠道FXR(iFXR)具有局限作用于肠道的优势,可避免全身释放所带来的副作用,在NAFLD的治疗上具有潜在的价值,但也存在一定的争议。综述了近年来iFXR在NAFLD的研究进展。
- 非酒精性脂肪性肝病 /
- 法尼醇X受体 /
- 胆酸类
Abstract:
The incidence rate of nonalcoholic fatty liver disease(NAFLD) is gradually increasing in recent years, and the treatment of NAFLD is unsatisfactory due to the failure in lifestyle adjustment and a lack of effective drugs. Farnesoid X receptor(FXR), as the main bile acid receptor, may affect NAFLD by participating in glucose and fat metabolism, and intestinal FXR(iFXR) acts on the intestinal tract alone and may thus avoid the side effects of systemic release. Therefore, it may have potential value in the treatment of NAFLD, but there are also certain controversies. This article reviews the research advances in the role of iFXR in NAFLD.
- non-alcoholic fatty liver disease /
- farnesol X receptor /
- cholic acids

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参考文献(40)

[1] YOUNOSSI ZM, KOENIG AB, ABDELATIF D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes[J]. Hepatology, 2016, 64(1):73-84.

[2] 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.

[3] 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.

[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] CAVE MC, CLAIR HB, HARDESTY JE, et al. Nuclear receptors and nonalcoholic fatty liver disease[J]. Biochim Biophys Acta, 2016, 1859(9):1083-1099.

[6] 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.

[7] RATZIU V, SANYAL AJ, LOOMBA R, et al. REGENERATE:Design of a pivotal, randomised, phase 3 study evaluating the safety and efficacy of obeticholic acid in patients with fibrosis due to nonalcoholic steatohepatitis[J]. Contemp Clin Trials,2019, 84:105803.

[8] 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.

[9] 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.

[10] LI T, CHIANG JY. Bile acid signaling in metabolic disease and drug therapy[J]. Pharmacol Rev, 2014, 66(4):948-983.

[11] MATSUBARA T, LI F, GONZALEZ FJ. FXR signaling in the enterohepatic system[J]. Mol Cell Endocrinol, 2013, 368(1-2):17-29.

[12] GOODWIN B, JONES SA, PRICE RR, et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis[J]. Mol Cel, 2000, 6(3):517-526.

[13] TANAKA N, AOYAMA T, KIMURA S, et al. Targeting nuclear receptors for the treatment of fatty liver disease[J]. Pharmacol Ther, 2017, 179:142-157.

[14] GONZALEZ FJ, JIANG C, XIE C, et al. Intestinal farnesoid X receptor signaling modulates metabolic disease[J]. Dig Dis,2017, 35(3):178-184.

[15] SAYIN SI, WAHLSTRÖM A, FELIN J, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist[J]. Cell Metab, 2013, 17(2):225-235.

[16] TURNBAUGH PJ, LEY RE, MAHOWALD MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest[J]. Nature, 2006, 444(7122):1027-1031.

[17] PAGADALA M, KASUMOV T, MCCULLOUGH AJ, et al. Role of ceramides in nonalcoholic fatty liver disease[J]. Trends Endocrinol Metab, 2012, 23(8):365-371.

[18] SUN R, YANG N, KONG B, et al. Orally administered berberine modulates hepatic lipid metabolism by altering microbial bile acid metabolism and the intestinal FXR signaling pathway[J]. Mol Pharmacol, 2017, 91(2):110-122.

[19] TEMEL RE, BROWN JM. A new model of reverse cholesterol transport:EnTICEing strategies to stimulate intestinal cholesterol excretion[J]. Trends Pharmacol Sci, 2015, 36(7):440-451.

[20] de BOER JF, SCHONEWILLE M, BOESJES M, et al. Intestinal farnesoid X receptor controls transintestinal cholesterol excretion in mice[J]. Gastroenterology, 2017, 152(5):1126-1138. e6.

[21] KIM YC, BYUN S, SEOK S, et al. Small heterodimer partner and fibroblast growth factor 19 inhibit expression of NPC1L1 in mouse intestine and cholesterol absorption[J]. Gastroenterology, 2019, 156(4):1052-1065.

[22] SUN L, PANG Y, WANG X, et al. Ablation of gut microbiota alleviates obesity-induced hepatic steatosis and glucose intolerance by modulating bile acid metabolism in hamsters[J].Acta Pharm Sin B, 2019, 9(4):702-710.

[23] JIANG C, XIE C, LV Y, et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction[J]. Nat Commun, 2015, 6:10166.

[24] LI F, JIANG C, KRAUSZ KW, et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity[J]. Nat Commun, 2013, 4:2384.

[25] van DIJK TH, GREFHORST A, OOSTERVEER MH, et al. An increased flux through the glucose 6-phosphate pool in enterocytes delays glucose absorption in Fxr-/-mice[J]. J Biol Chem, 2009, 284(16):10315-10323.

[26] 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.

[27] TRABELSI MS, DAOUDI M, PRAWITT J, et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells[J]. Nat Commun, 2015, 6:7629.

[28] FANG Q, LI H, SONG Q, et al. Serum fibroblast growth factor19 levels are decreased in Chinese subjects with impaired fasting glucose and inversely associated with fasting plasma glucose levels[J]. Diabetes Care, 2013, 36(9):2810-2814.

[29] KIR S, BEDDOW SA, SAMUEL VT, et al. FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis[J]. Science, 2011, 331(6024):1621-1624.

[30] LAN T, MORGAN DA, RAHMOUNI K, et al. FGF19, FGF21,and an FGFR1/β-Klotho-activating antibody act on the nervous system to regulate body weight and glycemia[J]. Cell Metab, 2017, 26(5):709-718. e3.

[31] PATHAK P, XIE C, NICHOLS RG, et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism[J].Hepatology, 2018, 68(4):1574-1588.

[32] XIE C, JIANG C, SHI J, et al. An intestinal farnesoid X receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice[J]. Diabetes, 2017, 66(3):613-626.

[33] DEGIROLAMO C, MODICA S, VACCA M, et al. Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptornull mice by intestinal-specific farnesoid X receptor reactivation[J]. Hepatology, 2015, 61(1):161-170.

[34] ARAGONÈS G, COLOM-PELLICER M, AGUILAR C, et al.Circulating microbiota-derived metabolites:A"liquid biopsy?[J]. Int J Obes(Lond), 2019.[Online ahead of print]

[35] ALISI A, CECCARELLI S, PANERA N, et al. Association between serum atypical fibroblast growth factors 21 and 19 and pediatric nonalcoholic fatty liver disease[J]. PLoS One,2013, 8(6):e67160.

[36] RINELLA ME, TROTTER JF, ABDELMALEK MF, et al. Rosuvastatin improves the FGF19 analogue NGM282-associated lipid changes in patients with non-alcoholic steatohepatitis[J]. J Hepatol, 2019, 70(4):735-744.

[37] LUO J, KO B, ELLIOTT M, et al. A nontumorigenic variant of FGF19 treats cholestatic liver diseases[J]. Sci Transl Med,2014, 6(247):247ra100.

[38] ZHOU M, LEARNED RM, ROSSI SJ, et al. Engineered FGF19eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice[J]. Hepatol Commun,2017, 1(10):1024-1042.

[39] WANG H, ZHAO Z, ZHOU J, et al. A novel intestinal-restricted FXR agonist[J]. Bioorg Med Chem Lett, 2017, 27(15):3386-3390.

[40] SUN L, XIE C, WANG G, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin[J]. Nat Med,2018, 24(12):1919-1929.

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