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Reduced Heart Size and Increased Myocardial Fuel Substrate Oxidation in ACC2 Mutant Mice
Author(s) -
AbuElheiga Lutfi A,
Essop M. Faadiel,
Sharma Saumya,
Camp Heidi S,
Fryer Rayan M,
Reinhart Glenn A,
Guthrie Patrick H,
Bentebibel Assia,
Teagtmeyer Heinrich,
Wakil salih J
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1356-c
Subject(s) - beta oxidation , pyruvate carboxylase , peroxisome , medicine , chemistry , carnitine palmitoyltransferase i , oxidative phosphorylation , endocrinology , ex vivo , wild type , acetyl coa carboxylase , downregulation and upregulation , genetically modified mouse , pyruvate dehydrogenase complex , cardiac function curve , transgene , mutant , biochemistry , fatty acid , biology , receptor , enzyme , gene , in vitro , heart failure
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.