JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
Add like
Add dislike
Add to saved papers

REV-ERB α Regulates CYP7A1 Through Repression of Liver Receptor Homolog-1.

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.

Full text links

We have located links that may give you full text access.
Can't access the paper?
Try logging in through your university/institutional subscription. For a smoother one-click institutional access experience, please use our mobile app.

For the best experience, use the Read mobile app

Mobile app image

Get seemless 1-tap access through your institution/university

For the best experience, use the Read mobile app

All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

By using this service, you agree to our terms of use and privacy policy.

Your Privacy Choices Toggle icon

You can now claim free CME credits for this literature searchClaim now

Get seemless 1-tap access through your institution/university

For the best experience, use the Read mobile app