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J. Biol. Chem., Vol. 280, Issue 27, 25629-25636, July 8, 2005

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Mitochondrial Glycerol-3-phosphate Acyltransferase-1 Is Essential in Liver for the Metabolism of Excess Acyl-CoAs^*

Linda E. Hammond, Susanne Neschen¶, Anthony J. Romanelli, Gary W. Cline, Olga R. Ilkayeva||, Gerald I. Shulman¶**, Deborah M. Muoio||, and Rosalind A. Coleman

From the Department of Nutrition, University of North Carolina, North Chapel Hill, Carolina 27599, the Department of Internal Medicine and^¶ Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, and the^|| Departments of Medicine and Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina 27710

In vitro studies suggest that the mitochondrial glycerol-3-phosphate acyltransferase-1 (mtGPAT1) isoform catalyzes the initial and rate-controlling step in glycerolipid synthesis and aids in partitioning acyl-CoAs toward triacylglycerol synthesis and away from degradative pathways. To determine whether the absence of mtGPAT1 would increase oxidation of acyl-CoAs and restrict the development of hepatic steatosis, we fed wild type and mtGPAT1^–/– mice a diet high in fat and sucrose (HH) for 4 months to induce the development of obesity and a fatty liver. Control mice were fed a diet low in fat and sucrose (LL). With the HH diet, absence of mtGPAT1 resulted in increased partitioning of acyl-CoAs toward oxidative pathways, demonstrated by 60% lower hepatic triacylglycerol content and 2-fold increases in plasma -hydroxybutyrate, acylcarnitines, and hepatic mRNA expression of mitochondrial HMG-CoA synthase. Despite the increase in fatty acid oxidation, liver acyl-CoA levels were 3-fold higher in the mtGPAT1^–/– mice fed both diets. A lack of difference in CPT1 and FAS mRNA expression between genotypes suggested that the increased acyl-CoA content was not because of increased de novo synthesis, but instead, to an impaired ability to use long-chain acyl-CoAs derived from the diet, even when the dietary fat content was low. Hyperinsulinemia and reduced glucose tolerance on the HH diet was greater in the mtGPAT1^–/– mice, which did not suppress the expression of the gluconeogenic genes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. This study demonstrates that mtGPAT1 is essential for normal acyl-CoA metabolism, and that the absence of hepatic mtGPAT1 results in the partitioning of fatty acids away from triacylglycerol synthesis and toward oxidation and ketogenesis.

Received for publication, March 23, 2005 , and in revised form, April 26, 2005.

^* This work was supported in part by Grants DK56598 (to R. A. C.), F31 GM20920 (to L. E. H.), K01 DK67200 (to D. M. M.), and DK40936 (to G. I. S.), P30 DK45735 (to G. I. S.), U24 DK59635 (to G. I. S.), and DK56350 to the University of North Carolina, CNRU. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** Recipient of a Distinguished Clinical Scientist Award from the American Diabetes Association and an Investigator of the Howard Hughes Medical Institute.

To whom correspondence should be addressed: Dept. of Nutrition, 2301 Hooker Research Bldg., University of North Carolina, Chapel Hill, NC 27599. Tel.: 919-966-7213; Fax: 919-966-7216; E-mail: rcoleman{at}unc.edu.

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