Project Grant R01ES033898

This three-year, $3.13 million project grant from the National Institutes of Health's National Institute of Environmental Health Sciences will fund research at Michigan State University investigating the progression of non-alcoholic fatty liver disease. Specifically, the grant will test the hypothesis that activation of the aryl hydrocarbon receptor by environmental contaminants reprograms fatty acid metabolism, causing the accumulation of toxic lipid intermediates that contribute to hepatotoxicity and the progression of steatosis to steatohepatitis with fibrosis.

The research team will use novel hepatocyte-specific aryl hydrocarbon receptor null mice to examine the role of octenoyl-coenzyme A, acrylyl-coenzyme A, and dicarboxylic acids in toxicity and disease severity. They will also investigate using cobalamin supplementation to protect against hepatotoxicity and disease progression, as well as study the role of itaconate in reducing cobalamin levels. Human hepatocyte cells will be used to evaluate the relevance of these findings to humans. The results aim to establish a mechanism by which aryl hydrocarbon receptor activation leads to differential gene expression, metabolic reprogramming and toxic metabolite biosynthesis contributing to liver damage and non-alcoholic fatty liver disease progression.