GPER-dependent estrogen signaling increases cardiac GCN5L1 expression and MCAD activity

Reversible lysine acetylation regulates the activity of cardiac metabolic enzymes, including those controlling fuel substrate metabolism. Mitochondrial-targeted GCN5L1 and SIRT3 have been shown to regulate the acetylation status of mitochondrial enzymes, which results in alterations to the relative oxidation rates of fatty acids, glucose, and other fuels for contractile activity. However, the role that lysine acetylation plays in driving metabolic differences between male and female hearts is not currently known. In this study, we report that estrogens induce the expression of GCN5L1 via GPER agonism in cardiac cells, which increases the enzymatic activity and acetylation status of the fatty acid oxidation enzyme medium chain acyl-CoA dehydrogenase (MCAD).