REV-ERBα and REV-ERBβ are heme regulated nuclear receptors that are known to regulate metabolic pathways. We previously demonstrated that treatment of mice with synthetic REV-ERB agonists suppressed plasma cholesterol levels and the hepatic levels of the rate limiting enzyme in cholesterol biosynthesis (3-hydroxy-3-methylglutaryl-CoA reductase). Here, we characterize the role of REV-ERB on the cholesterol biosynthetic pathway in greater detail. The REV-ERB agonist SR9009 reduced plasma cholesterol levels in both wild type C57Bl/6 and low density lipoprotein receptor (LDLR) null mice as well as reducing the expression of an array of genes within the cholesterol biosynthetic pathway. Consistent with these data, we observed increased expression of these genes in mice deficient in expression of Rev-erbα. Analysis of global run-on and deep sequencing (GRO-Seq) and chromatin immunoprecipitation deep sequencing (ChIP-Seq) data revealed that Rev-erb directly binds to the majority of genes involved in cholesterol biosynthesis and directly suppresses their expression. This study reveals insight into the complex mechanism by which Rev-erb directly and indirectly (via inhibition of Srebf2 expression) regulates cholesterol biosynthesis and provides information of how cholesterol levels are regulated in a circadian fashion. Additionally, these studies suggest that targeting Rev-erb may be an effective method for suppressing LDL cholesterol levels in the clinic.
Keywords: Atherosclerosis; Cholesterol synthesis; Nuclear receptor; Rev-erb; Statins.
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