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J. Biol. Chem., Vol. 281, Issue 2, 945-950, January 13, 2006

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Rat Long Chain Acyl-CoA Synthetase 5 Increases Fatty Acid Uptake and Partitioning to Cellular Triacylglycerol in McArdle-RH7777 Cells^*

From the Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599

Long chain acyl-CoA synthetase (ACSL) catalyzes the initial step in long chain fatty acid metabolism. Of the five mammalian ACSL isoforms cloned and characterized, ACSL5 is the only isoform found to be located, in part, on mitochondria and thus was hypothesized to be involved in fatty acid oxidation. To elucidate the specific roles of ACSL5 in fatty acid metabolism, we used adenoviral-mediated overexpression of ACSL5 (Ad-ACSL5) in rat hepatoma McArdle-RH7777 cells. Confocal microscopy revealed that Ad-ACSL5 colocalized to both mitochondria and endoplasmic reticulum. When compared with cells infected with Ad-GFP, Ad-ACSL5-infected cells at 24 h after infection had 2-fold higher acyl-CoA synthetase activities and 30% higher rates of fatty acid uptake when incubated with 500 µM [1-¹⁴C]oleic acid. Metabolism of [1-¹⁴C]oleic acid to cellular triacylglycerol (TAG) increased 42% in Ad-ACSL5-infected cells, but when compared with control cells, metabolism to acid-soluble metabolites, phospholipids, and medium TAG did not differ substantially. The incorporation of [1-¹⁴C]oleate and [1,2,3-³H]glycerol into TAG was similar in Ad-ACSL5-infected cells, thus indicating that Ad-ACSL5 increased TAG synthesis through both de novo and reacylation pathways. However, [1-¹⁴C]acetic acid incorporation into cellular lipids showed that, when compared with control cells, Ad-ACSL5-infected cells did not increase the metabolism of fatty acids that were derived from de novo synthesis. These results suggest that uptake of fatty acids into cells is regulated by metabolism and that overexpressed ACSL5 partitions exogenously derived fatty acids toward TAG synthesis and storage.

Received for publication, July 14, 2005 , and in revised form, October 31, 2005.

^* This work was supported by National Institutes of Health Grants DK68993 (to D. G. M.), DK61190 (to C. G. V. H.), and DK59935 (to R. A. C.). 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.

¹ To whom correspondence should be addressed: Dept. of Nutrition, CB 7461, 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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