# Effects of Dietary Fat on the Hepatotoxicity of Environmental Arsenic

> **NIH NIH P20** · UNIVERSITY OF LOUISVILLE · 2020 · $163,681

## Abstract

One of every three American adults is obese and is afflicted with some form of non-alcoholic fatty liver disease
(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. Our previous studies have shown that
consumption of arsenic-contaminated drinking water is an important risk factor for progression of NAFLD.
Preliminary proteomic analysis demonstrated that the abundance of a number of proteins that are controlled at
the transcriptional level by HNF-4a was decreased in the livers of mice with arsenic-enhanced NAFLD.
Mechanistic studies showed that the expression of this zinc finger transcription factor was not altered, but that
its DNA binding activity was inhibited at the post-translational level. HNF-4a is known to be regulated by posttranslational
modifications (PTMs), and arsenic has the potential to affect zinc binding, cysteine oxidation,
arginine methylation and lysine acetylation. Very little is known about how PTMs of HNF-4a are regulated, or
how disruption of these regulatory processes contributes to liver disease. To follow up on these important
findings, the objective of the current proposal is to delineate the mechanisms by which environmental arsenic
exposure promotes the progression from steatosis to steatohepatitis in mice fed a Western-style diet that is
high in saturated fat. The central hypothesis to be tested is that alterations in HNF-4a-mediated gene
expression induced by arsenic play a critical role in the progression of NAFLD from steatosis to steatohepatitis
in this model. This hypothesis will be tested in three Specific Aims. First, we will define the specific molecular
interactions of arsenic with the zinc finger domain of HNF-4a. Second, we will analyze the mechanisms by
which arsenic affects PTMs of HNF-4a, and how these changes translate into altered DNA binding activity and
transactivation potential. Third, we will define the post-translational modifications of hepatic HNF-4a in mice fed
a high fat diet and exposed to arsenic-contaminated drinking water, and relate these changes to the occupancy
of HNF-4a-response elements in genes involved in lipid metabolism and inflammation. This model of
inflammatory liver injury is relevant to the United States population, where high fat diets are common and
arsenic exposure levels are typically below the threshold for overt hepatotoxicity. The new information obtained
from these studies will delineate pathways that are altered by arsenic and that are important in the etiology of
NAFLD.

## Key facts

- **NIH application ID:** 10115956
- **Project number:** 5P20GM113226-05
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** WALTER H WATSON
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $163,681
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115956

## Citation

> US National Institutes of Health, RePORTER application 10115956, Effects of Dietary Fat on the Hepatotoxicity of Environmental Arsenic (5P20GM113226-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10115956. Licensed CC0.

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