Lysine Acetyltransferase 6A in Health and Cardiac Diseases

PROJECT SUMMARY Pathological hypertrophy can progress to failing heart. During the transition, fatty acid utilization is decreased, while utilization of other substrates, such as ketone body, is increased. Multiple lines of evidence indicate that increased myocardial ketone body utilization is an adaptive response against cardiac pathology. Furthermore, although ketoacidosis is life-threatening, short-term administration of exogenous ketone body enhances myocardial oxygen consumption with increases in both ketone body oxidation and overall ATP production in the heart. This intervention improves cardiac function and remodeling in humans and mice with heart failure (HF). Although ketone body serves as not only a fuel source but a modulator of lysine acetylation, the effect of ketone body-mediated acetylation against hypertrophy and HF remains poorly understood. Elucidating the molecular mechanisms of ketone body action beyond fueling, which mediates anti-hypertrophic and pro- energetic effects without provoking detrimental effects, is the most important issue in establishing ketone body as a therapeutic option for HF. We recently found that lysine acetyltransferase 6A (KAT6A) is acetylated in the heart by a low-carbohydrate (LC) diet-mediated increase in ketone body, which is negatively associated with hypertrophy and HF after pressure overload. Thus, we here ask whether acetylation of KAT6A is critically involved in ketone body action against cardiac pathology. Our study provided evidence that acetylation of KAT6A inhibits phenylephrine-induced hypertrophy and improves energy homeostasis in cardiomyocytes in vitro. However, it remains unknown how KAT6A acetylation regulates cardiac morphology and function. Based on these exciting observations we propose a novel role of KAT6A acetylation in pathological hypertrophy and its transition to HF. Together with the surprising findings from our studies using proteomics and genomics analyses, we hypothesize that ketone body promotes acetylation of KAT6A, which stimulates the AMPK signaling in the heart to suppress protein synthesis and maintain energy homeostasis, thereby inhibiting pathological hypertrophy and a transition to HF. To address this hypothesis, we will conduct the following experiments. In Aim 1, we will determine the significance of KAT6A acetylation in pressure overload-induced hypertrophy and HF in vivo by using newly generated KAT6A acetylation-resistant knock-in mice and an AAV- KAT6A acetylation-mimicking mutant. In Aim 2, we will demonstrate the critical involvement of AMPK in KAT6A action by pharmacologically and genetically inhibiting AMPK. We will further elucidate the mechanism by which AMPK is activated by KAT6A by using molecular signaling and biological assays. The long-term goal of this project is to identify the therapeutic targets to specifically modulate the ketone body-KAT6A-AMPK pathway relevant to the strategies for the primary and secondary prevention of cardiac hypertrophy and HF.