REV-ERBα Regulates CYP7A1 Through Repression of Liver Receptor Homolog-1
2017
Nuclear heme receptor reverse erythroblastosis virus (REV-ERB) α (a transcriptional repressor) is known to regulate cholesterol 7 α -hydroxylase (CYP7A1) and bile acid synthesis. However, the mechanism for REV-ERB α regulation of CYP7A1 remains elusive. Here, we investigate the role of LRH-1 in REV-ERB α 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-erb α /REV-ERB α antagonist using cell-based assays and confirmed expression of Rev-erb α in mouse liver. GSK2945 treatment increased hepatic mouse cholesterol 7 α -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-erb α /REV-ERB α target gene. Furthermore, conditional deletion of Lrh-1 in the liver abrogated the regulatory effects of Rev-erb α on Cyp7a1 and cholesterol metabolism in mice. In conclusion, Rev-erb α regulates Cyp7a1 and cholesterol metabolism through its repression of the Lrh-1 receptor. Targeting the REV-ERB α /LRH-1 axis may represent a novel approach for management of cholesterol-related diseases.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
40
References
39
Citations
NaN
KQI