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

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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.