Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Mitchell A. Lazar

Second Advisor

Klaus H. Kaestner

Abstract

Circadian and metabolic physiology are intricately intertwined. Although the liver clock is entrained by the central clock, it also directly controls metabolic gene expression. Hormone responsive nuclear factors are hypothesized to be the major clock components that regulate metabolism, which include Rev-erbs and RORs. In this study, we explored the mechanism of regulation of liver circadian gene expression by Rev-erbs and RORs. We found that Rev-erbalpha modulates the clock and metabolism by different genomic mechanisms. Clock control requires Rev-erbalpha to bind directly to the genome at its cognate sites, where it competes with activating ROR TFs. By contrast, Rev-erbalpha regulates metabolic genes primarily by recruiting the HDAC3 corepressor to sites to which it is tethered by cell type-specific transcription factors. Thus, direct competition between Rev-erbalpha and ROR TFs provides a universal mechanism for self-sustained control of molecular clock across all tissues, whereas Rev-erbalpha utilizes�lineage-determining factors to convey a tissue-specific epigenomic rhythm that regulates metabolism tailored to the specific need of that tissue.

In addition, we also investigate the circadian regulation of hepatic metabolism by nuclear receptors RORalpha and RORgamma. We discovered that hepatic depletion of RORs increased expressions of genes involved in lipogenesis as well as the hepatic triglyceride levels, specifically at ZT22 (5 AM) and during feeding, but not at ZT10 (5 PM) nor during fasting. GRO-seq analysis suggested that regulation of lipid metabolism by RORs was mediated by SREBP1-c. Indeed, ROR depletion significantly up-regulated nuclear SREBP1-c protein level specifically at ZT22. Overall, our study reveals a time-specific regulation of liver lipid metabolism by RORs, and suggests a potential role of chronotherapy targeting circadian factors in the treatment of metabolic disorders.

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