Alcohol, nuclear receptor signaling, and circadian clocks

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DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) ranges from steatosis to cirrhosis and is a major cause of chronic liver diseases. The circadian system comprises a complex feedback network that involves interactions between the central nervous system and peripheral tissues. Disturbance of circadian rhythmicity is a risk factor for the development of ALD. However, the association between circadian clocks and ALD remains largely unexplored. In addition, the most advanced analytical tools, such as transcriptomics (RNA-seq) and metabolomics (GC/MS), have not been well utilized to study ALD. Nuclear receptors are key mediators between the molecular clock machinery and metabolic diseases. My laboratory has made pioneering discoveries regarding the in vivo function of small heterodimer partner (SHP) and has recently uncovered a critical role for SHP in the integration of the liver clock and metabolic network. The objective of this application is to determine the role of the liver and/or central clock and clock- controlled genes in alcohol-induced fatty liver disease associated with disruption of rhythmicity of hepatic metabolites. The hypothesis of this application is that alcoho induced fatty liver is mediated by liver/central clock genes via SHP-dependent and SHP-independent mechanisms. Aim #1: To build comprehensive hepatic circadian networks and discover oscillatory metabolites regulated by ethanol- binge in a SHP dependent and independent fashion; and Aim #2: To establish central circadian networks regulated by ethanol-binge in a SHP dependent and independent fashion. We will use a simple ethanol- binge model developed by Dr. Bin Gao at NIAAA and our unique SHP-/- mice under different environmental cues (light/dark cycles). The rhythmic expression of genes in the liver regulated by ethanol-binge will be analyzed by next generation RNA-sequencing, while the diurnal variations of plasma and liver metabolites will be determined by GC/MS metabolomics analysis. The anticipated result is establishing the entire liver transcriptome and metabolome affected by alcohol-binge. The study will provide fundamental knowledge required to establish a crucial link between the liver/central clock and alcoholic fatty liver. Therefore, the innovative research proposed is expected to enable substantial advances in ALD research, making this project of high clinical significance and of high relevance to the mission of NIAAA.