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Originally published In Press as doi:10.1194/jlr.M400010-JLR200 on April 21, 2004

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Journal of Lipid Research, Vol. 45, 1279-1288, July 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Overexpression of mitochondrial GPAT in rat hepatocytes leads to decreased fatty acid oxidation and increased glycerolipid biosynthesis

Daniel Lindén*,{dagger}, Lena William-Olsson*, Magdalena Rhedin*, Anna-Karin Asztély*, John C. Clapham* and Sandra Schreyer1,*

* AstraZeneca R&D, Mölndal, Sweden
{dagger} Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Sweden

1 To whom correspondence should be addressed. e-mail: sandra.schreyer{at}astrazeneca.com

Glycerol-3-phosphate acyltransferase (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. Because both mtGPAT and carnitine palmitoyl transferase-1 are located on the outer mitochondrial membrane, we hypothesized that mtGPAT directs fatty acyl-CoA away from ß-oxidation and toward 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 >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.

Abbreviations: CHO, Chinese hamster ovary; CPT-1, carnitine palmitoyl transferase-1; ER, endoplasmic reticulum; GPAT, glycerol-3-phosphate acyltransferase; MOI, multiplicity of infection; wt, wild type

Supplementary key words glycerol-3-phosphate acyltransferase • obesity • triglyceride


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