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Mol. Cell. Biol. doi:10.1128/MCB.01122-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Hepatic de novo lipogenesis is present in liver-specific ACC1 deficient mice

Departments of Pharmacology and Metabolic Disorder Research, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan

^* To whom correspondence should be addressed. Email: jun_kusunoki{at}merck.com.

	Abstract

Acetyl-CoA carboxylase (ACC) catalyzes carboxylation of acetyl-CoA to form malonyl-CoA. In mammals, two isozymes exist with each distinct physiological role: cytosolic ACC1 participates in de novo lipogenesis (DNL); and mitochondrial ACC2 is involved in negative regulation of mitochondrial -oxidation. Since systemic ACC1 null mice were embryonic lethal, to clarify the physiological role of ACC1 in hepatic DNL, we generated the liver-specific ACC1 null mouse by crossbreeding of Acc1^lox(ex48) mouse in which exon 46 of Acc1 was flanked by two loxP sequences and liver-specific Cre transgenic mouse. In liver-specific ACC1 null mice, neither hepatic Acc1 mRNA nor protein was detected. However, to compensate ACC1 function, hepatic ACC2 protein and activity were induced by 1.4 and 2.2 times, respectively. Surprisingly, hepatic DNL and malonyl-CoA were maintained at as the same physiological levels as in wild-type mice. Furthermore, hepatic DNL was completely inhibited by an ACC1/2 dual inhibitor, 2, 5-(tetradecyloxyl)-2-furancarboxylic acid (TOFA). These results strongly demonstrate that malonyl-CoA from ACC2 can access to fatty acid synthase and become the substrate for the DNL pathway under the unphysiological circumstances that result with ACC1 disruption. Therefore, there does not appear to be strict compartmentalization of malonyl-CoA from either of the ACC isozymes in the liver.

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