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(The FASEB Journal. 2007;21:949.9)
© 2007 FASEB
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949.9

Reduced Heart Size and Increased Myocardial Fuel Substrate Oxidation in ACC2 Mutant Mice

Lutfi A Abu-Elheiga1, M. Faadiel Essop2, Saumya Sharma3, Heidi S Camp4, Rayan M Fryer4, Glenn A Reinhart4, Patrick H Guthrie3, Assia Bentebibel1, Heinrich Teagtmeyer3 and salih J Wakil1

1 Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030,
2 Faculty of Health Sciences, University of Cape Town, Observatory, 7925, CapeTown, South Africa,
3 Division of Cardiology, University of Texas-Houston Medical School, 6431 Fannin, Houston, TX, 77030,
4 Abbott Laboratory, 100 Abbott Park Road, Abbott Park, IL, 60064

ABSTRACT

Acetyl-CoA carboxylase (ACC2) is a key regulator of mitochondrial fatty acid (FA) uptake via carnitine palmitoyltransferase 1 (CPT1). In order to test the hypothesis that oxidative metabolism is upregulated in hearts from amice lacking ACC2 (employing a transgenic Acc2-mutant mice), 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%). In isolated, retrogradely perfused hearts of MUT mice myocardial oxygen consumption (MVO2) was about 25% higher than the wildtype. Rates of oleate oxidation were increased by 22%. Unexpectedly, rates of glucose oxidation were two fold higher in the MUT hearts. In parallel, transcript levels of peroxisome proliferator-activated receptor alpha (PPARa) and its target genes, pyruvate dehydrogenase kinase 4 and mCPT1 were, surprisingly, downregulated in MUT vs. WT mice. We propose that modulation of PPARa activation in the MUT mouse heart may be an adaptive response to prevent excessive cardiac FA oxidation and thereby preserving contractile function.





This Article
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