Abstract 11526: Lysine Acetylation Enhances Cardiac Fatty Acid ß-Oxidation
Fatty acids β-oxidation (FAO) is a major source of energy for the adult heart.
However, excessive rates of FAO can compromise cardiac function in obesity, diabetes, reperfusion following ischemia, and heart failure (HF). Recently, lysine acetylation has emerged as a novel post-translational pathway that regulates the activity of a number of metabolic enzymes, including those involved in FAO. In mitochondria, this post-translational acetylation is catalyzed by general control of amino acid synthesis 5-like 1 (GCN5L1), while SIRT3is a major deacetylase. Despite the fact that a number of FAO enzymes can be acetylated, whether this post-translational modification activates or inhibits FAO enzymes is a matter of debate. We therefore examined the role of lysine acetylation on FAO in hearts from diet-induced obese mice, abdominal aortic constriction-induced HF obese mice, and in mice hearts subjected to ischemia and reperfusion. High FAO rates in isolated working hearts from diet-induced obese mice was found to be positively correlated with an increase in activity of the FAO enzymes, long chain acyl CoA dehydrogenase (LCAD) and β-hydroxyacyl CoA dehydrogenase (β-HAD). An increase in LCAD and β-HAD acetylation was also observed, which was associated with a decrease in SIRT3 expression and no change in the expression of GCN5L1. In hearts from obese HF mice, FAO provided over 92% of the heart ATP production, which was associated with an increase in the acetylation and activity of LCAD. Cardiac SIRT3 expression was not changed in obese-HF mice, but GCN5L1 was significantly increased in obese-HF mice. In reperfused ischemic hearts, acetylation of β-HAD was significantly increased compared to non-ischemic heart; a scenario associated with high FAO. We conclude that increased lysine acetylation activates rather than inhibits the activity of cardiac FAO enzymes. This can adversely increase FAO in the stressed heart.
- © 2013 by American Heart Association, Inc.