REGULATING MYOCARDIAL FATTY ACID OXIDATION IN DIABETES

University Of Tennessee Health Sci Ctr, Memphis TN

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Abstract

The heart preferentially uses fatty acids as an energy source for muscle contraction, although it can utilize glucose, ketone bodies and lactate. In diabetic cardiomyopathy the heart is forced to use fatty acids even though the high rate of fatty acid oxidation is detrimental to heart function. The genetic and biochemical mechanisms producing diabetic cardiomyopathy are not understood. They involve altered expression patterns of different isoforms of many proteins including enzymes of metabolism and the contractile proteins. Fatty acid oxidation inhibitors [especially carnitine palmitoyltransferase-I (CPT-I) inhibitors] increase glucose oxidation and limit fatty acid oxidation in the diabetic heart with subsequent improvement of heart function. CPT-I is widely recognized as the primary physiological control point in the fatty acid oxidation pathway. CPT-I is regulated by transcriptional control and by its physiological inhibitor, malonyl-CoA. Two isoforms of CPT-I are known, CPT-Ialpha and CPT-IBeta. The heart is unique in possessing both isoforms. Insulin causes hepatic CPT-Ialpha, but not muscle CPT-IBeta, to become much more sensitive to malonyl-CoA inhibition. In hearts perfused with glucose, insulin increases malonyl-CoA concentration many times higher than it can in liver, effecting the same control in the two tissues by different mechanisms. The mechanisms by which insulin regulates CPT-I transcription are not known, but they plan to examine these mechanisms in this proposal. The applicants have cloned the CPT-Ia gene, and they are characterizing CPT-Ia promoter elements and the nuclear transcription factors which control CPT-Ia expression in the liver and heart. The research indicates that CPT-Ia is overexpressed in both liver and heart, a potentially pathological event resulting in increased hepatic fatty acid oxidation that increases hyperglycemia and decreases myocardial pyruvate oxidation. The mechanism controlling myocardial changes in CPT-I isoform expression in the diabetic state is not yet understood, nor is it known what specific functions the two CPT-I isoforms perform in the heart. To examine regulation of the two CPT-I isoforms, the following specific aims are proposed: (1) to examine the effects of diabetes on CPT-Ialpha gene expression in vivo using transgenic mouse lines and a rat genetic model of heart failure, (2) to characterize the regulation of CPT-Ialpha gene transcription in the heart in the normal and diabetic state by defining promoter elements and transcription factors specific for the heart, and (3) to examine differential regulation by fatty acids of CPT-Ialpha gene expression in liver and heart.