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Papers In Press, published online ahead of print April 21, 2004
J. Lipid Res., doi:10.1194/jlr.M400010-JLR200
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Department of Molecular Pharmacology, AstraZeneca R&D, Mölndal, Molndal 431 83
Corresponding Author: Sandra.Schreyer{at}astrazeneca.com
Glycerol-3-phosphate acyl transferase (GPAT) catalyses the first committed step in glycerolipid biosynthesis. The mitochondrial isoform (mtGPAT) is mainly expressed in liver where it is highly regulated, indicating that mtGPAT may have a unique role in hepatic fatty acid metabolism. Since both mtGPAT and carnitine palmitoyl transferase-1 (CPT-1) are located on the outer mitochondrial membrane, we hypothesized that mtGPAT directs fatty acyl-CoA away from beta-oxidation and towards glycerolipid synthesis. Adenoviral-mediated overexpression of murine mtGPAT in primary cultures of rat hepatocytes increased mtGPAT activity 2.7-fold with no compensatory effect on microsomal GPAT activity. MtGPAT overexpression resulted in a dramatic 80% reduction in fatty acid oxidation and a significant increase in hepatic diacylglycerol and phospholipid biosynthesis. Following lipid loading of the cells, intracellular triacylglycerol biosynthesis was also induced by mtGPAT overexpression. Changing an invariant aspartic acid residue to a glycine [D235G] in mtGPAT resulted in an inactive enzyme which helps define the active site required for mammalian mtGPAT function. To determine if obesity increases hepatic mtGPAT activity, two models of rodent obesity were examined and shown to have over 2-fold increased enzyme activity. Overall, these results support the concept that increased hepatic mtGPAT activity associated with obesity positively contributes to lipid disorders by reducing oxidative processes and promoting de novo glycerolipid synthesis.
Revised on March 30, 2004
Accepted on April 7, 2004
Overexpression of mitochondrial glycerol-3-phosphate acyltransferase in rat hepatocytes leads to decreased fatty acid oxidation and increased glycerolipid biosynthesis
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