胆固醇7α羟化酶
心理压抑
内分泌学
内科学
生物
法尼甾体X受体
核受体
胆固醇
化学
基因
基因表达
生物化学
转录因子
医学
作者
Tianpeng Zhang,Mengjing Zhao,Danyi Lu,Shuai Wang,Fangjun Yu,Lianxia Guo,Shijun Wen,Baojian Wu
标识
DOI:10.1124/dmd.117.078105
摘要
Nuclear heme receptor reverse erythroblastosis virus (REV-ERB) α (a transcriptional repressor) is known to regulate cholesterol 7α-hydroxylase (CYP7A1) and bile acid synthesis. However, the mechanism for REV-ERBα regulation of CYP7A1 remains elusive. Here, we investigate the role of LRH-1 in REV-ERBα regulation of CYP7A1 and cholesterol metabolism. We first characterized the tertiary amine N-(4-chloro-2-methylbenzyl)-N-(4-chlorobenzyl)-1-(5-nitrothiophen-2-yl)methanamine (GSK2945) as a highly specific Rev-erbα/REV-ERBα antagonist using cell-based assays and confirmed expression of Rev-erbα in mouse liver. GSK2945 treatment increased hepatic mouse cholesterol 7α-hydroxylase (Cyp7a1) level and lowered plasma cholesterol in wild-type mice. Likewise, the compound increased the expression and microsomal activity of Cyp7a1 in hypercholesterolemic mice. This coincided with reduced plasma and liver cholesterol and enhanced production of bile acids. Increased levels of Cyp7a1/CYP7A1 were also found in mouse and human primary hepatocytes after GSK2945 treatment. In these experiments, we observed parallel increases in Lrh-1/LRH-1 (a known hepatic activator of Cyp7a1/CYP7A1) mRNA and protein. Luciferase reporter, mobility shift, and chromatin immunoprecipitation assays revealed that Lrh-1/LRH-1 was a direct Rev-erbα/REV-ERBα target gene. Furthermore, conditional deletion of Lrh-1 in the liver abrogated the regulatory effects of Rev-erbα on Cyp7a1 and cholesterol metabolism in mice. In conclusion, Rev-erbα regulates Cyp7a1 and cholesterol metabolism through its repression of the Lrh-1 receptor. Targeting the REV-ERBα/LRH-1 axis may represent a novel approach for management of cholesterol-related diseases.
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