Role of Acetyl-CoA Synthetase 2 and Acetyl-CoA Precursors, Acetate and Ethanol, on Hepatocyte Gene Expression

Abnormally high blood and tissue lipid levels observed in metabolic disorders and cardiovascular diseases are associated with extensive gene expression changes. Gene expression is modulated by epigenetic mechanisms, which include modifications of DNA-bound protein histones without alteration of DNA sequence. Histone hyperacetylation is observed in the setting of metabolic disorders but the causes have not been described in any detail. We know that histone acetylation is positively correlated with the abundance of acetyl-coenzyme A. This study tests the hypothesis that acetyl-coenzyme A metabolizing enzyme acetyl-coenzyme A synthetase 2 (ACSS2, cytoplasmic, aka AceCS1) impacts liver function through histone acetylation, and that dietary precursors of acetyl-CoA (acetate and ethanol) further contribute to these effects. Our long-term goal is to understand mechanistic relationships between diet and histone modification particularly where they present opportunities for the prevention and treatment of cardiovascular disease risk factors