Effects of Dietary Fat on the Hepatotoxicity of Environmental Arsenic

Overview

One of every three American adults is obese and has some form of NAFLD. The majority of obese individuals will have steatosis (fatty liver), but only about 20% will have the more serious condition of steatohepatitis (fatty liver with inflammation and liver injury). There is still no FDA-approved therapy for any stage of NAFLD. Therefore, it is critical that we understand the multiple factors that promote progression from steatosis to steatohepatitis in NAFLD. Previous studies suggest that consumption of arsenic-contaminated drinking water is one such factor. The objective of the current proposal is to delineate the mechanisms by which environmental arsenic exposure promotes progression from steatosis to steatohepatitis. Preliminary data demonstrate that HNF-4α activity is impaired at the post-translational level in arsenic-enhanced NAFLD. HNF-4α is a zinc finger transcription factor that controls the expression of a large number of genes, including genes involved in fat metabolism and inflammation. Arsenic has the potential to affect all of the PTMs known to alter HNF-4α activity, including zinc binding, cysteine oxidation and arginine methylation.

Hypothesis

Alterations in HNF-4a-mediated gene expression induced by arsenic play a critical role in the progression of NAFLD from steatosis to steatohepatitis.

Dietary Fat & Environmental Arsenic Lead to NASH Hypothesisleads toboth lead to Drinking Water Arsenic Altered structure of HNF-4a zinc finger Zinc finger metallation Cysteine oxidation Arginine methylation Lysine acetylation Altered HNF-4a promoter occupancy Altered expression of genes Lipid metabolism Inflammation High Fat Diet Fatty Liver NASH

About Researcher

Principal Investigator

Walter Watson

Walter Watson, PhD

Assistant Professor of Medicine

E-mail Dr. Watson

Education

PostDoc
Toxicology & Biochemistry, Emory University School of Medicine
PhD
University of Kentucky School of Medicine

Related Project

Effect of Dietary Fat on the Hepatotoxicity of Environmental Arsenic