All ETDs from UAB

Advisory Committee Chair

Shannon M Bailey

Advisory Committee Members

Victor Darley-Usmar

Karen L Gamble

Aimee Landar

Anath Shalev

Martin E Young

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Chronic alcohol consumption has been shown to significantly decrease hepatic glycogen, an important storage form of energy for the body and liver. Emerging studies indicate a link between metabolism and the molecular circadian clock. Previously, we have shown that chronic alcohol consumption disrupts the liver molecular clock mechanism. However, it is not known how this alteration impacts hepatic energy (e.g., glycogen) metabolism and contributes to alcohol hepatotoxicity. This dissertation investigates the impact chronic alcohol consumption has on time-of-day-dependent oscillations of various aspects of liver glycogen metabolism, and the importance of the liver circadian clock in these metabolic alterations. Chapter 1: Introduction and Background provides an overview on several areas important to this dissertation, including alcoholic liver disease, glycogen metabolism, and circadian clocks. Chapter 2: Material and Methods gives a detailed description of the dissertation study design and strategies used to assess chronic alcohol-mediated disruption of hepatic glycogen metabolism. Chapter 3: Chronic ethanol consumption disrupts diurnal rhythms of hepatic glycogen metabolism in mice presents findings showing that chronic alcohol consumption significantly alters the diurnal rhythm of glycogen in the liver. Furthermore, chronic ethanol consumption disrupted time-of-day-dependent oscillations of gene expression, phosphorylated and total protein abundance, and activities of glycogen regulatory enzymes. These findings suggest that chronic alcohol-mediated dysregulation of these daily rhythms likely contributes to glycogen depletion, which could contribute, in part, to impaired hepatic energy homeostasis. Chapter 4: Hepatocyte-specific deletion of the essential circadian clock transcription factor BMAL1 enhances chronic ethanol-mediated depletion of hepatic glycogen in mice explores the role of the liver circadian clock, which drives daily rhythms in metabolism, in chronic alcohol-induced glycogen depletion. Here we show that genetic disruption of hepatocyte clock function enhances the impact chronic ethanol consumption has on liver glycogen by completely abolishing its daily oscillation. We also found that several key carbohydrate metabolism genes in the liver may be under direct transcriptional regulation by the hepatocyte molecular clock. Taken together, our findings indicate that disruption of the hepatocyte circadian clock in mice alters glycogen metabolic processes in the liver, and enhances alcohol-dependent depletion of glycogen content, an important energy source.

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