Date on Master's Thesis/Doctoral Dissertation

12-2023

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, MS

Committee Chair

Watson, Walter

Committee Member

States, J. Christopher

Committee Member

Hood, Joshua

Author's Keywords

alcohol,; chrna4; nicotinic; lipogenic; Sirt1; liver

Abstract

Alcohol-associated liver disease (ALD) is a broad spectrum of diseases ranging from steatosis to severe hepatic cirrhosis, none of which have any FDA approved therapies. Downregulation of hepatic Sirtuin 1 (Sirt1) activity by ethanol has been shown to lead to an upregulation of the pro-lipogenic gene targets under its jurisdiction, resulting in increased lipogenesis and triglyceride accumulation. It was hypothesized that ethanol acts on α4*-nicotinic acetylcholine receptors (α4*-nAChRs) in hepatocytes to decrease Sirt1 expression, which ultimately dysregulates lipid metabolic homeostasis. Ethanol’s effects were investigated in cultured AML12 hepatocytes and in WT primary mouse hepatocytes acutely exposed to ethanol. Consistent with the hypothesized mechanism of action, ethanol treated hepatocytes showed a significant decrease in Sirt1 mRNA expression and an increase in subsequent lipogenic genes compared to untreated cells. Pre-treatment with α4*-nAChR inhibitor, dihydro-β-erythroidine, blocked ethanol’s downregulation of Sirt1 and the subsequent upregulation of its downstream targets. Taken together, these data support a role for α4*-nAChRs expressed by hepatocytes in mediating the early effects of ethanol on the liver.

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