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.

Public Health Relevance

The balance between pro- and anti-oxidant mechanisms plays a role in liver toxicity for all drugs and chemicals. This study uses mouse and human models to evaluate a novel cellular defense mechanism following exposure to synthetic, natural, and endogenous ligands of the aryl hydrocarbon receptor in the development and progression of non-alcoholic fatty liver disease (NAFLD).

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
3R01ES029541-02S1
Application #
10240420
Study Section
Systemic Injury by Environmental Exposure (SIEE)
Program Officer
Shreffler, Carol A
Project Start
2020-09-01
Project End
2024-03-31
Budget Start
2020-09-01
Budget End
2021-03-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Michigan State University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824