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

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

  • Drug Metab Dispos. 2018 Mar;46(3):248-258. doi: 10.1124/dmd.117.078105.
Tianpeng Zhang 1 Mengjing Zhao 1 Danyi Lu 1 Shuai Wang 1 Fangjun Yu 1 Lianxia Guo 1 Shijun Wen 1 Baojian Wu 2
Affiliations

Affiliations

  • 1 Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy (T.Z., M.Z., D.L., S.W., F.Y., L.G., B.W.), and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research (T.Z., B.W.), Jinan University, Guangzhou, China; and School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (S.W.).
  • 2 Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy (T.Z., M.Z., D.L., S.W., F.Y., L.G., B.W.), and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research (T.Z., B.W.), Jinan University, Guangzhou, China; and School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (S.W.) bj.wu@hotmail.com.
Abstract

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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