# Toxic lipid intermediate accumulation and cobalamin depletion promote AHR-mediated hepatotoxicity and the progression of non-alcoholic fatty liver disease (NAFLD)-like pathologies

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2022 · $1,565,100

## Abstract

Abstract:
Non-alcoholic fatty liver disease (NAFLD) describes a spectrum of pathologies which typically involves simple,
reversible hepatic fat accumulation (steatosis) progressing into steatohepatitis with fibrosis that increases the
risk for more complex metabolic diseases. NAFLD prevalence is projected to increase from ~83 million in 2015
to ~101 million by 2030 in the US alone. Accumulating evidence suggests environmental contaminants play an
underappreciated role in NAFLD development and progression. Many chemicals induce fatty liver, but the
environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and related compounds, exhibit the
greatest potency. Most, if not all, of the effects induced by TCDD are mediated by the aryl hydrocarbon
receptor (AHR). We have shown that TCDD induces the progression of steatosis to steatohepatitis (non-
alcoholic steatohepatitis (NASH)) with fibrosis, however the underlying mechanisms are poorly understood
beyond AHR activation and subsequent changes in gene expression. Our integration of preliminary RNAseq
and metabolomics data suggests multiple AHR-mediated effects converge to cause to cause hepatotoxicity
and the progression of NAFLD-like pathologies including the repression of hepatic fatty acid oxidation,
increased bile acid levels, immune cell infiltration and decreased serum cobalamin (Cbl, aka Vitamin B12)
levels. This proposal will test the hypothesis that AHR activation reprograms fatty acid metabolism causing the
accumulation of toxic intermediates that contribute to hepatotoxicity and the progression of steatosis to
steatohepatitis with fibrosis. In vivo and in vitro genetic and pharmacological approaches will be to further
investigate the role of octenoyl-CoA, acrylyl-CoA and dicarboxylic acids (DCAs). Specific Aim 1 will use novel
hepatocyte-specific AHR null mice to show that hepatic octenoyl-CoA, acrylyl-CoA and DCAs contribute to
hepatotoxicity and NAFLD pathology severity. Specific Aim 2 will use (i) Cbl supplementation to protect against
hepatotoxicity and NAFLF progression and (ii) Acod1 null mice to investigate the role of itaconate (Ita) in
reducing Cbl levels. Specific Aim 3 will use human HepaRG cells to determine the relevance of AHR-mediated
metabolic reprogramming and the accumulation of toxic intermediate metabolites. These results will establish a
mechanism that involves AHR-mediated differential gene expression, metabolic reprograming and the
biosynthesis of toxic metabolites that contribute to the hepatotoxicity and NAFLD progression. We will show
that Cbl supplementation can protect against AHR-mediated hepatotoxicity. Cbl supplementation will also
prove to be an effective countermeasure to protect exposed populations susceptible to AHR-mediated
hepatotoxicity that may also be beneficial in the treatment and management of NAFLD.

## Key facts

- **NIH application ID:** 10391942
- **Project number:** 1R01ES033898-01
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Timothy R. Zacharewski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,565,100
- **Award type:** 1
- **Project period:** 2022-09-03 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10391942

## Citation

> US National Institutes of Health, RePORTER application 10391942, Toxic lipid intermediate accumulation and cobalamin depletion promote AHR-mediated hepatotoxicity and the progression of non-alcoholic fatty liver disease (NAFLD)-like pathologies (1R01ES033898-01). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10391942. Licensed CC0.

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