# Project 3 - The role of HMGCR in Modulating TCDD-induced, AHR-mediated NAFLD

> **NIH NIH P42** · MICHIGAN STATE UNIVERSITY · 2024 · $302,577

## Abstract

PROJECT SUMMARY/ABSTRACT
Hypercholesterolemia, obesity, non-alcoholic fatty liver disease (NAFLD), and diabetes have increased in the
US population to epidemic proportions. Accumulating epidemiological evidence and rodent studies link
environmental pollutants and dietary chemicals to NAFLD progression. Many environmental contaminants,
including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds are ligands for the aryl
hydrocarbon receptor (AhR). TCDD also disrupts the expression of genes involved in metabolism such as 3-
Hydroxy-3-Methylglutaryl-Coenzyme A Reductase (HMGCR), the rate-limiting step in cholesterol biosynthesis.
Interestingly, environmental exposure to TCDD and related compounds decrease serum cholesterol levels in
humans which has been linked to metabolic dysfunction, hepatotoxicity and NAFLD progression. Preliminary
studies also show that inhibition of HMGCR activity via statin co-treatment decreased TCDD-induced
hepatosteatosis, but exacerbated TCDD-induced toxicity. Collectively, these results suggest a strong
relationship between AHR activation, cholesterol homeostasis and NAFLD progression. This has led us to
hypothesize that changes in cholesterol homeostasis alters sensitivity to TCDD and related compound
elicited hepatotoxicity and NAFLD pathogenesis. Specific Aim 1 will use in vitro experiments examining the
link between AHR signaling, HMGCR activity, and intermediate metabolism. Specific Aim 2 will examine the
effects of TCDD on HMGCR activity in the absence and presence of simvastatin co-exposure, during AHR-
mediated progression from steatosis to steatohepatitis with fibrosis. Results from these specific aims will be
integrated to elucidate the cell-specific metabolic changes that affect TCDD-induced hepatotoxicity and NAFLD
progression. Collaborations with Project 1 (Kaminski) and Project 2 (Johnson), will further characterize the role
of infiltrating immune cell populations and the impact of TCDD on hepatocyte mitochondria and energetics.
These studies will also determine if prescribed statin type drugs increase the risk of hepatotoxicity and NAFLD
development due to persistent exposure to TCDD and related compounds. Currently, more than 40 million
Americans are prescribed statins every year. Consequently, the importance of assessing this risk cannot be
overstated, and warrants further investigation.

## Key facts

- **NIH application ID:** 10877989
- **Project number:** 5P42ES004911-29
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Timothy R. Zacharewski
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $302,577
- **Award type:** 5
- **Project period:** 1997-04-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877989

## Citation

> US National Institutes of Health, RePORTER application 10877989, Project 3 - The role of HMGCR in Modulating TCDD-induced, AHR-mediated NAFLD (5P42ES004911-29). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10877989. Licensed CC0.

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