Abstract P247: APPL1 Transgenic Mice Are Protected from High-Fat Diet--Induced Lipotoxic Cardiomyopathy

Abstract

Increased circulating levels of free fatty acid (FA) in obesity and diabetes lead to the accumulation of FA in non-adipose tissue such as myocardium and this is known to be a major contributor to cardiomyopathy. In this present study, we investigated the role of APPL1 (Adaptor protein containing PH domain, PTB domain and Leucine zipper motif-1), an important regulator of insulin signaling, in a model of high fat diet (HFD) induced cardiomyopathy. We fed APPL1 transgenic (Tg) or wild type (wt) mice a high fat (60% kcal) or normal chow diet. After 16 weeks, in wt mice HFD induced hyperinsulinemia and hyperlipidemia, as well as cardiac dysfunction determined by echocardiography system (Vevo 2100). Furthermore, HFD induced cardiac insulin resistance and acetyl CoA carboxylase (ACC) phosphorylation. Lipid analysis using LC/MS/MS showed HFD significantly increased intracellular level of distinct ceramide and diacylglycerol (DAG) species in heart tissue. Interestingly, HFD fed APPL1 Tg mice showed a relatively normal circulating level of FA and improved insulin sensitivity in heart tissue, compared to the wt mice. Lipid analysis indicated that APPL1 Tg mice had approximately 20% reduced intra-myocardial accumulation of ceramides and DAGs after HFD compared to wt mice. APPL1 Tg mice also showed better cardiac performance in ejection fraction and cardiac output under these conditions. In summary, here we demonstrated that APPL1 Tg mice are protected from HFD-induced increases in circulating levels of FA, accumulation of lipotoxic fatty acid derivatives and insulin resistance in myocardial tissue and deterioration in cardiac function.