-
摘要: 法尼醇X受体（Farnesoid X receptor，FXR），又称胆汁酸受体，因与代谢调节密切相关，FXR激动剂目前成为代谢性疾病治疗的药物研发热点。FXR天然激动剂来源广泛且大部分具有无或低毒副作用的特点，主要分为动物源性激动剂、植物源性激动剂和微生物源性激动剂三大类。动物源性激动剂包括鹅脱氧胆酸、胆酸、脱氧胆酸、石胆酸和熊去氧胆酸等内源性胆汁酸，以及雄甾酮；植物源性激动剂包括植物和植物提取物，如泽泻提取物、咖啡醇、香豆雌酚、葡萄内脂和薯蓣皂苷；微生物源性激动剂包括细格菌素。本文就FXR天然激动剂的研究进展进行综述。Abstract: Due to the significant association of Farnesoid X receptor (FXR) with metabolic regulation, FXR agonists have become a hotspot for drug research and development in the treatment of metabolic diseases. FXR natural agonists have a wide range of sources and most of them have the characteristics of no or low side effects. They are mainly divided into three categories: animal-derived agonists, plant-derived agonists and microbial-derived agonists. Animal-derived agonists include endogenous bile acids such as chenodeoxycholic acid, cholic acid, deoxycholic acid, lithocholic acid and ursodeoxycholic acid as well as androsterone; plant-derived agonists include plants and plant extracts, such as Alisma extract, caffeol, couestrol, grape lactone and dioscin; microbial-derived agonists include serotonin. This article reviews the research progress of FXR natural agonists.
-
Keywords:
- Farnesoid X receptor /
- bile acid receptor /
- natural agonist
-
-
[1] Shin DJ, Wang L. Bile Acid-Activated Receptors: A Review on FXR and Other Nuclear Receptors[J]. Handb Exp Pharmacol, 2019, 256: 51-72. DOI:10.1007/164_2019_236.
[2] Garcia M, Thirouard L, Sedès L, et al. Nuclear receptor metabolism of bile acids and xenobiotics: a coordinated detoxification system with impact on health and diseases[J]. Int J Mol Sci, 2018, 19(11): E3630. DOI:10.3390/ijms19113630.
[3] Massafra V, van Mil SWC. Farnesoid X receptor: a "homeostat" for hepatic nutrient metabolism[J]. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(1): 45-59. DOI:10.1016/j.bbadis.2017.10.003.
[4] Younossi ZM, Ratziu V, Loomba R, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial[J]. Lancet, 2019, 394(10215): 2184-2196. DOI:10.1016/S0140-6736(19)33041-7.
[5] Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease[J]. Gastroenterology, 2013, 145(3): 574-582. e1. DOI:10.1053/j.gastro.2013.05.042.
[6] Bowlus CL, Pockros PJ, Kremer AE, et al. Long-term obeticholic acid therapy improves histological endpoints in patients with primary biliary cholangitis[J]. Clin Gastroenterol Hepatol, 2020, 18(5): 1170-1178. e6. DOI:10.1016/j.cgh.2019.09.050.
[7] Flatt B, Martin R, Wang TL, et al. Discovery of XL335(WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR)[J]. J Med Chem, 2009, 52(4): 904-907. DOI:10.1021/jm8014124.
[8] Gai Z, Chu L, Xu Z, et al. Farnesoid X receptor activation protects the kidney from ischemia-reperfusion damage[J]. Sci Rep, 2017, 7(1): 9815. DOI:10.1038/s41598-017-10168-6.
[9] Zhao K, He JL, Zhang Y, et al. Activation of FXR protects against renal fibrosis via suppressing Smad3 expression[J]. Sci Rep, 2016, 6: 37234. DOI:10.1038/srep37234.
[10] Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis[J]. N Engl J Med, 2016, 375(7): 631-643. DOI:10.1056/nejmoa1509840.
[11] Di Ciaula A, Garruti G, Lunardi Baccetto R, et al. Bile acid physiology[J]. Ann Hepatol, 2017, 16(suppl. 1: s3-105. ): s4-s14. DOI:10.5604/01.3001.0010.5493.
[12] Kast HR, Nguyen CM, Sinal CJ, et al. Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids[J]. Mol Endocrinol, 2001, 15(10): 1720-1728. DOI:10.1210/mend.15.10.0712.
[13] Li C, Li J, Weng X, et al. Farnesoid X receptor agonist CDCA reduces blood pressure and regulates vascular tone in spontaneously hypertensive rats[J]. J Am Soc Hypertens, 2015, 9(7): 507-516. e7. DOI:10.1016/j.jash.2015.04.006.
[14] European Association for the Study of the Liver. EASL Clinical Practice Guidelines: the diagnosis and management of patients with primary biliary cholangitis[J]. J Hepatol, 2017, 67(1): 145-172. DOI:10.1016/j.jhep.2017.03.022.
[15] Hirschfield GM, Dyson JK, Alexander GJM, et al. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines[J]. Gut, 2018, 67(9): 1568-1594. DOI:10.1136/gutjnl-2017-315259.
[16] Lew JL, Zhao AN, Yu JH, et al. The farnesoid X receptor controls gene expression in a ligand- and promoter-selective fashion[J]. J Biol Chem, 2004, 279(10): 8856-8861. DOI:10.1074/jbc.M306422200.
[17] 唐清, 王琳琳, 单庆文, 等. 熊去氧胆酸对婴儿胆汁淤积性肝炎多药耐药蛋白3及法尼醇受体基因表达的影响和意义[J]. 中国当代儿科杂志, 2013, 15(9): 756-758. DOI:10.7499/j.issn.1008-8830.2013.09.011.
[18] Zhang YY, LaCerte C, Kansra S, et al. Comparative potency of obeticholic acid and natural bile acids on FXR in hepatic and intestinal in vitro cell models[J]. Pharmacol Res Perspect, 2017, 5(6): e00368. DOI:10.1002/prp2.368.
[19] Mueller M, Thorell A, Claudel T, et al. Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity[J]. J Hepatol, 2015, 62(6): 1398-1404. DOI:10.1016/j.jhep.2014.12.034.
[20] 黎源, 马锦星, 石朝周. 鸡胆汁与蛇胆汁中主要结合胆汁酸的含量对比[J]. 中成药, 2003, 25(5): 420-421. DOI:10.3969/j.issn.1001-1528.2003.05.029.
[21] Uchida A, Yamada T, Hayakawa T, et al. Taurochenodeoxycholic acid ameliorates and ursodeoxycholic acid exacerbates small intestinal inflammation[J]. Am J Physiol, 1997, 272(5 Pt 1): G1249-G1257. DOI:10.1152/ajpgi.1997.272.5.G1249.
[22] Arndt H, Kullmann F, Schölmerich J, et al. Acute and chronic effects of different bile acids on indomethacin-induced intestinal inflammation[J]. Inflammation, 1997, 21(6): 553-567. DOI:10.1023/A:1027390920570.
[23] 李欣, 牛春宇, 毛伟, 等. TCDCA对大鼠脂肪代谢及其相关受体FXR表达量的影响[J]. 中国兽医学报, 2018, 38(7): 1430-1434, 1456. DOI:10.16303/j.cnki.1005-4545.2018.07.30.
[24] 张捷, 张超峰, 龚庆豪, 等. DCA对FXR的作用及结肠癌细胞生物学行为的影响[J]. 结直肠肛门外科, 2016, 22(2): 199-202. https://www.cnki.com.cn/Article/CJFDTOTAL-DCGM201602025.htm
[25] Wang S, Lai K, Moy FJ, et al. The nuclear hormone receptor farnesoid X receptor (FXR) is activated by androsterone[J]. Endocrinology, 2006, 147(9): 4025-4033. DOI:10.1210/en.2005-1485.
[26] Chao F, Gong W, Li Y, et al. Effect of androsterone on scavenger receptor class B type I in human vascular endothelial cells[J]. Nan Fang Yi Ke Da Xue Xue Bao, 2009, 29(7): 1344-1347. http://europepmc.org/abstract/MED/19620049
[27] 程龙艳, 贾会玉, 陈光亮. 丹蛭降糖胶囊治疗2型糖尿病实验与临床研究进展[J]. 中医药临床杂志, 2014, 26(08): 870-872. DOI:10.16448/j.cjtcm.2014.08.040
[28] 李建会, 韩群英, 荆志伟, 等. 二黄降糖汤联合西药治疗气阴两虚证2型糖尿病并血脂代谢紊乱30例[J]. 中医研究, 2016, 29(06): 16-18. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYYJ201606008.htm
[29] Huo XK, Liu J, Yu ZL, et al. Alisma orientale extract exerts the reversing cholestasis effect by activation of farnesoid X receptor[J]. Phytomedicine, 2018, 42: 34-42. DOI:10.1016/j.phymed.2018.03.017.
[30] Meng Q, Chen X, Wang C, et al. Protective effects of alisol B23-acetate from edible botanical Rhizoma alismatis against carbon tetrachloride-induced hepatotoxicity in mice[J]. Food Funct, 2015, 6(4): 1241-1250. DOI:10.1039/c5fo00082c.
[31] Meng Q, Duan XP, Wang CY, et al. Alisol B23-acetate protects against non-alcoholic steatohepatitis in mice via farnesoid X receptor activation[J]. Acta Pharmacol Sin, 2017, 38(1): 69-79. DOI:10.1038/aps.2016.119.
[32] Lin HR. Triterpenes from Alisma orientalis act as farnesoid X receptor agonists[J]. Bioorg Med Chem Lett, 2012, 22(14): 4787-4792. DOI:10.1016/j.bmcl.2012.05.057.
[33] Urgert R, Katan MB. The cholesterol-raising factor from coffee beans[J]. Annu Rev Nutr, 1997, 17: 305-324. DOI:10.1146/annurev.nutr.17.1.305.
[34] Woo SM, Min KJ, Seo BR, et al. Cafestol overcomes ABT-737 resistance in Mcl-1-overexpressed renal carcinoma Caki cells through down-regulation of Mcl-1 expression and upregulation of Bim expression[J]. Cell Death Dis, 2014, 5(11): e1514. DOI:10.1038/cddis.2014.472.
[35] van Vlijmen BJ, van den Maagdenberg AM, Gijbels MJ, et al. Diet-induced hyperlipoproteinemia and atherosclerosis in apolipoprotein E3-Leiden transgenic mice[J]. J Clin Invest, 1994, 93(4): 1403-1410. DOI:10.1172/jci117117.
[36] Post SM, de Roos B, Vermeulen M, et al. Cafestol increases serum cholesterol levels in apolipoprotein E*3-leiden transgenic mice by suppression of bile acid synthesis[J]. Arterioscler Thromb Vasc Biol, 2000, 20(6): 1551-1556. DOI:10.1161/01.atv.20.6.1551.
[37] Boekschoten MV, Engberink MF, Katan MB, et al. Reproducibility of the serum lipid response to coffee oil in healthy volunteers[J]. Nutr J, 2003, 2: 8. DOI:10.1186/1475-2891-2-8.
[38] Ricketts ML, Boekschoten MV, Kreeft AJ, et al. The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors[J]. Mol Endocrinol, 2007, 21(7): 1603-1616. DOI:10.1210/me.2007-0133.
[39] Kanayama T, Mamiya S, Nishihara T, et al. Basis of a high-throughput method for nuclear receptor ligands[J]. J Biochem, 2003, 133(6): 791-797. DOI:10.1093/jb/mvg101.
[40] Takahashi M, Kanayama T, Yashiro T, et al. Effects of coumestrol on lipid and glucose metabolism as a farnesoid X receptor ligand[J]. Biochem Biophys Res Commun, 2008, 372(3): 395-399. DOI:10.1016/j.bbrc.2008.04.136.
[41] Mori H, Niwa K, Zheng Q, et al. Cell proliferation in cancer prevention; effects of preventive agents on estrogen-related endometrial carcinogenesis model and on an in vitro model in human colorectal cell[J]. Mutat Res, 2001, 480-481: 201-207. DOI:10.1016/s0027-5107(01)00200-7.
[42] 杨秀伟, 徐波, 冉福香, 等. 40种香豆素类化合物对人胃癌细胞株BGC和人肝癌细胞株BEL-7402细胞生长抑制活性的筛选[J]. 中国现代中药, 2006, 8(11): 7. DOI:10.13313/j.issn.1673-4890.2006.11.003
[43] Kuroyanagi K, Kang MS, Goto T, et al. Citrus auraptene acts as an agonist for PPARs and enhances adiponectin production and MCP-1 reduction in 3T3-L1 adipocyt[J]. Biochem Biophys Res Commun, 2008, 366(1): 219-225. DOI:10.1016/j.bbrc.2007.11.119.
[44] Epifano F, Molinaro G, Genovese S, et al. Neuroprotective effect of prenyloxycoumarins from edible vegetables[J]. Neurosci Lett, 2008, 443(2): 57-60. DOI:10.1016/j.neulet.2008.07.062.
[45] Gao XG, Fu T, Wang CY, et al. Computational discovery and experimental verification of farnesoid X receptor agonist auraptene to protect against cholestatic liver injury[J]. Biochem Pharmacol, 2017, 146: 127-138. DOI:10.1016/j.bcp.2017.09.016.
[46] Li H, Huang W, Wen Y, et al. Anti-thrombotic activity and chemical characterization of steroidal saponins from Dioscorea zingiberensis C.H. Wright[J]. Fitoterapia, 2010, 81(8): 1147-1156. Doi:10.1016/j.fitote.2010.07.016.
[47] Hsieh MJ, Tsai TL, Hsieh YS, et al. Dioscin-induced autophagy mitigates cell apoptosis through modulation of PI3K/Akt and ERK and JNK signaling pathways in human lung cancer cell lines[J]. Arch Toxicol, 2013, 87(11): 1927-1937. Doi:10.1007/s00204-013-1047-z.
[48] Cho J, Choi H, Lee J, et al. The antifungal activity and membrane-disruptive action of dioscin extracted from Dioscorea nipponica[J]. Biochim Biophys Acta, 2013, 1828(3): 1153-1158. Doi:10.1016/j.bbamem.2012.12.010.
[49] Lu B, Xu Y, Xu L, et al. Mechanism investigation of dioscin against CCl4-induced acute liver damage in mice[J]. Environ Toxicol Pharmacol, 2012, 34(2): 127-135. Doi:10.1016/j.etap.2012.03.010.
[50] Tao X, Wan X, Xu Y, et al. Dioscin attenuates hepatic ischemia-reperfusion injury in rats through inhibition of oxidative-nitrative stress, inflammation and apoptosis[J]. Transplantation, 2014, 98(6): 604-611. Doi:10.1097/TP.0000000000000262.
[51] Tao X, Sun X, Yin L, et al. Dioscin ameliorates cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via HMGB-1 inhibition[J]. Free Radic Biol Med, 2015, 84: 103-115. Doi:10.1016/j.freeradbiomed.2015.03.003.
[52] Qi M, Zheng L, Qi Y, et al. Dioscin attenuates renal ischemia/reperfusion injury by inhibiting the TLR4/MyD88 signaling pathway via up-regulation of HSP70[J]. Pharmacol Res, 2015, 100: 341-352. Doi:10.1016/j.phrs.2015.08.025.
[53] Liu M, Xu Y, Han X, et al. Dioscin alleviates alcoholic liver fibrosis by attenuating hepatic stellate cell activation via the TLR4/MyD88/NF-κB signaling pathway[J]. Sci Rep, 2015, 5: 18038. Doi:10.1038/srep18038.
[54] Zhang YM, Xu YW, Qi Y, et al. Protective effects of dioscin against doxorubicin-induced nephrotoxicity via adjusting FXR-mediated oxidative stress and inflammation[J]. Toxicology, 2017, 378: 53-64. DOI:10.1016/j.tox.2017.01.007.
[55] Nakanishi S, Toki S, Saitoh Y, et al. Isolation of myosin light chain kinase inhibitors from microorganisms: dehydroaltenusin, altenusin, atrovenetinone, and cyclooctasulfur[J]. Biosci Biotechnol Biochem, 1995, 59(7): 1333-1335. DOI:10.1271/bbb.59.1333.
[56] Zheng ZH, Zhao ZM, Li SQ, et al. Altenusin, a nonsteroidal microbial metabolite, attenuates nonalcoholic fatty liver disease by activating the farnesoid X receptor[J]. Mol Pharmacol, 2017, 92(4): 425-436. DOI:10.1124/mol.117.108829.
计量
- 文章访问数: 1536
- PDF下载数: 253
- 施引文献: 0
下载: