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J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M900218-JLR200 on June 17, 2009

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Journal of Lipid Research, Vol. 50, 2502-2513, December 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

A novel role for fatty acid transport protein 1 in the regulation of tricarboxylic acid cycle and mitochondrial function in 3T3-L1 adipocytes

Brian M. Wiczer and David A. Bernlohr1

Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN

To whom correspondence should be addressed. e-mail: bernl001{at}umn.edu

Fatty acid transport proteins (FATPs) are integral membrane acyl-CoA synthetases implicated in adipocyte fatty acid influx and esterification. Whereas some FATP1 translocates to the plasma membrane in response to insulin, the majority of FATP1 remains within intracellular structures and bioinformatic and immunofluorescence analysis of FATP1 suggests the protein primarily resides in the mitochondrion. To evaluate potential roles for FATP1 in mitochondrial metabolism, we used a proteomic approach following immunoprecipitation of endogenous FATP1 from 3T3-L1 adipocytes and identified mitochondrial 2-oxoglutarate dehydrogenase. To assess the functional consequence of the interaction, purified FATP1 was reconstituted into phospholipid-containing vesicles and its effect on 2-oxoglutarate dehydrogenase activity evaluated. FATP1 enhanced the activity of 2-oxoglutarate dehydrogenase independently of its acyl-CoA synthetase activity whereas silencing of FATP1 in 3T3-L1 adipocytes resulted in decreased activity of 2-oxoglutarate dehydrogenase. FATP1 silenced 3T3-L1 adipocytes exhibited decreased tricarboxylic acid cycle activity, increased cellular NAD+/NADH, increased fatty acid oxidation, and increased lactate production indicative of altered mitochondrial energy metabolism. These results reveal a novel role for FATP1 as a regulator of tricarboxylic acid cycle activity and mitochondrial function.

Supplementary key words fatty acid transport proteins • mitochondria • reconstitution • oxidation • proteomics • alpha-ketoglutarate dehydrogenase • redox homeostasis

Abbreviations: ASM, acid soluble metabolites; DDM, n-dodecyl-β-D-maltoside; DOPC, dioleoylphosphatidylcholine; DOPE, dioleoylphosphatidylethanolamine; DOPS, dioleoylphosphatidyl-L-serine; FATP, fatty acid transport protein; LCFA, long-chain fatty acid; OGDH, 2-oxoglutarate dehydrogenase complex; PDH, pyruvate dehydrogenase, shRNA, short hairpin RNA; SUV, small unilamellar vesicle


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