All ETDs from UAB

Advisory Committee Chair

Shannon M Bailey

Advisory Committee Members

Karen L Gamble

Adam R Wende

Scott W Ballinger

David M Pollock

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Hepatic Steatosis, characterized by the accumulation of triglyceride (TG) in the liver is the first stage of Alcoholic Liver Disease (ALD) and Nonalcoholic Fatty Liver Disease (NAFLD). Many metabolic pathways, including lipid metabolism, are regulated by the molecular circadian clock. Importantly, alcohol consumption and obesity induce circadian clock disruption, a risk factor for many diseases, including liver disease. In our first study, we investigated the combined effect of clock disruption and alcohol feeding on liver pathology, and diurnal rhythms in the liver molecular clock and lipid metabolism. Male liver-specific Bmal1 knockout (LKO) mice and control littermates were fed a control or alcohol-containing diet. After 5 weeks, livers were collected every 4 h and used for measurements of molecular clock and lipid metabolism genes and proteins, liver and plasma TG, histopathology, and FA composition of the hepatic TG lipidome. A second study examined the impact of short-term time restricted (TRF) feeding on high fat (HF)-induced alterations in diurnal rhythms of molecular clock and energy metabolism genes. For these studies, male C57BL6/J mice were fed normal (10% fat) or HF (45% fat) diets with ad lib access for 18 weeks, after which mice were placed on a TRF protocol, in which food availability was restricted to the dark phase. In this dissertation, we provide evidence that genetic deletion of the liver clock worsens alcohol-induced steatosis and markers of liver injury. Alcohol and/or clock disruption also differentially impact liver and plasma TG and induce numerous alterations in the hepatic TG lipidome. We also offer novel observations supporting the efficacy of short-term TRF as a therapeutic intervention to improve lipid handling and clock gene disruption by reversing abnormal diurnal rhythms in Bmal1, Cry2, and Nr1d1/REV-ERBα in livers of mice fed a HF diet. We also show that HF alters diurnal mRNA rhythms in energy metabolism genes in the liver of mice, with TRF preventing alterations in metabolic gene mRNA rhythms, such as Nfil3/E4BP4 and Nrip1/RIP140. Together, these studies advance understanding of the importance of the molecular clock in the pathogenesis of ALD and NAFLD.

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