# AhR-dependent Pkm2 regulation in NAFLD progression

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2020 · $65,838

## Abstract

Project Summary
The mechanism of toxicity for the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD) and related compounds remains poorly understood, beyond activation of the aryl
hydrocarbon receptor (AhR). TCDD induces xenobiotic metabolizing enzymes with subsequent
increases in reactive oxygen species (ROS). Epidemiological and rodent studies have further
implicated AhR activation in the development and progression of non-alcoholic fatty liver disease
(NAFLD). Our preliminary data demonstrates that AhR ligands induce a novel antioxidant
mechanism involving the expression of the pyruvate kinase M2 (PKM2) isoform. PKM2
expression causes metabolic reprogramming that redirects accumulating glycolytic intermediates
to the pentose phosphate pathway (PPP) and serine biosynthesis to increase NADPH levels and
glutathione production in of support cellular antioxidant responses. This proposal will establish a
mechanistic link between AhR activation, metabolic reprogramming, antioxidant defenses, and
progression of NAFLD pathologies in mouse and human models by (1) demonstrating AhR
regulation of Pkm2 expression, (2) tracking the redirection of 13C-glucose and 13C-glutamine
intermediates to the PPP and glutathione biosynthesis, and (3) investigating the antioxidant role
of Pkm2 in the progression of hepatic steatosis to steatohepatitis with fibrosis, modulation of tumor
surveillance immune cell populations, and dysbiosis of the gut microbiome. Collectively, these
studies will demonstrate that AhR-mediated PKM2 induction is a novel cellular defense
mechanism, and represents a major advancement in the elucidation of the hepatotoxicity of TCDD
and related compounds, with a focus on the development and progression of NAFLD.

## Key facts

- **NIH application ID:** 10240420
- **Project number:** 3R01ES029541-02S1
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Timothy R. Zacharewski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,838
- **Award type:** 3
- **Project period:** 2020-09-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240420

## Citation

> US National Institutes of Health, RePORTER application 10240420, AhR-dependent Pkm2 regulation in NAFLD progression (3R01ES029541-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10240420. Licensed CC0.

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