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1Department of Physiological Sciences, Stellenbosch University, Stellenbosch; 2Hatter Heart Research Institute, University of Cape Town Faculty of Health Sciences, Cape Town, South Africa; 3Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park; 4Departments of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; 5Department of Internal Medicine, Division of Cardiology, University of Texas-Houston Medical School, Houston; 6Department of Integrative Pharmacology, Abbott Laboratories, Abbott Park, Illinois; 7Verna and Mars McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas; and 8Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Barcelona, Spain
Submitted 18 December 2007 ; accepted in final form 28 April 2008
The cardiac-enriched isoform of acetyl-CoA carboxylase (ACC2) is a key regulator of mitochondrial fatty acid (FA) uptake via carnitine palmitoyltransferase 1 (CPT1). To test the hypothesis that oxidative metabolism is upregulated in hearts from animals lacking ACC2 (employing a transgenic Acc2-mutant mouse), we assessed cardiac function in vivo and determined rates of myocardial substrate oxidation ex vivo. When examined by echocardiography, there was no difference in systolic function, but left ventricular mass of the Acc2-mutant (MUT) mouse was significantly reduced (
25%) compared with wild-types (WT). Reduced activation of the mammalian target of rapamycin (mTOR) and its downstream target p70S6K was found in MUT hearts. Exogenous oxidation rates of oleate were increased 22%, and, unexpectedly, exogenous glucose oxidation rates were also increased in MUT hearts. Using a hyperinsulinemic-euglycemic clamp, we found that glucose uptake in MUT hearts was increased by 83%. Myocardial triglyceride levels were significantly reduced in MUT vs. WT while glycogen content was the same. In parallel, transcript levels of PPAR
and its target genes, pyruvate dehydrogenase kinase-4 (PDK-4), malonyl-CoA decarboxylase (MCD), and mCPT1, were downregulated in MUT mice. In summary, we report that 1) Acc2-mutant hearts exhibit a marked preference for the oxidation of both glucose and FAs coupled with greater utilization of endogenous fuel substrates (triglycerides), 2) attenuated mTOR signaling may result in reduced heart sizes observed in Acc2-mutant mice, and 3) Acc2-mutant hearts displayed normal functional parameters despite a significant decrease in size.
acetyl-CoA carboxylase; fatty acid β-oxidation; glucose oxidation; PPAR
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