葡萄糖醛酸化
鹅去氧胆酸
胆固醇7α羟化酶
肝X受体
胆酸
胆汁酸
CYP8B1
化学
胆汁淤积
G蛋白偶联胆汁酸受体
核受体
生物化学
氧甾醇
葡萄糖醛酸转移酶
CYP27A1
酶
生物
胆固醇
内分泌学
基因
微粒体
转录因子
作者
Mélanie Verreault,Kathy Senekeo‐Effenberger,Jocelyn Trottier,Jessica A. Bonzo,Julie Bélanger,Jenny Kaeding,Bart Staels,Patrick Caron,Robert H. Tukey,Olivier Barbier
出处
期刊:Hepatology
[Wiley]
日期:2006-08-01
卷期号:44 (2): 368-378
被引量:64
摘要
Glucuronidation, an important bile acid detoxification pathway, is catalyzed by enzymes belonging to the UDP-glucuronosyltransferase (UGT) family. Among UGT enzymes, UGT1A3 is considered the major human enzyme for the hepatic C24-glucuronidation of the primary chenodeoxycholic (CDCA) and secondary lithocholic (LCA) bile acids. We identify UGT1A3 as a positively regulated target gene of the oxysterol-activated nuclear receptor liver X-receptor alpha (LXRalpha). In human hepatic cells and human UGT1A transgenic mice, LXRalpha activators induce UGT1A3 mRNA levels and the formation of CDCA-24glucuronide (24G) and LCA-24G. Furthermore, a functional LXR response element (LXRE) was identified in the UGT1A3 promoter by site-directed mutagenesis, electrophoretic mobility shift assays and chromatin immunoprecipitation experiment. In addition, LXRalpha is found to interact with the SRC-1alpha and NCoR cofactors to regulate the UGT1A3 gene, but not with PGC-1beta. In conclusion, these observations establish LXRalpha as a crucial regulator of bile acid glucuronidation in humans and suggest that accumulation of oxysterols in hepatocytes during cholestasis favors bile acid detoxification as glucuronide conjugates. LXR agonists may be useful for stimulating both bile acid detoxification and cholesterol removal in cholestatic or hypercholesterolemic patients, respectively.
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