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J. Biol. Chem., Vol. 280, Issue 11, 10817-10826, March 18, 2005

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Long-chain Acyl-CoA Synthetase 6 Preferentially Promotes DHA Metabolism^*

Joseph R. Marszalek, Claire Kitidis, Concetta C. DiRusso¶||, and Harvey F. Lodish**

From the Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, the ^**Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, and ^¶Ordway Research Institute, Inc. and ^||The Albany Medical College, Albany, New York 12208

Previously we demonstrated that supplementation with the polyunsaturated fatty acids (PUFA) arachidonic acid (AA) or docosahexaenoic acid (DHA) increased neurite outgrowth of PC12 cells during differentiation, and that overexpression of rat acyl-CoA synthetase long-chain family member 6 (Acsl6, formerly ACS2) further increased PUFA-enhanced neurite outgrowth. However, whether Acsl6 overexpression enhanced the amount of PUFA accumulated in the cells or altered the partitioning of any fatty acids into phospholipids (PLs) or triacylglycerides (TAGs) was unknown. Here we show that Acsl6 overexpression specifically promotes DHA internalization, activation to DHA-CoA, and accumulation in differentiating PC12 cells. In contrast, oleic acid (OA) and AA internalization and activation to OA-CoA and AA-CoA were increased only marginally by Acsl6 overexpression. Additionally, the level of total cellular PLs was increased in Acsl6 overexpressing cells when the medium was supplemented with AA and DHA, but not with OA. Acsl6 overexpression increased the incorporation of [¹⁴C]-labeled OA, AA, or DHA into PLs and TAGs. These results do not support a role for Acsl6 in the specific targeting of fatty acids into PLs or TAGs. Rather, our data support the hypothesis that Acsl6 functions primarily in DHA metabolism, and that its overexpression increases DHA and AA internalization primarily during the first 24 h of neuronal differentiation to stimulate PL synthesis and enhance neurite outgrowth.

Received for publication, October 15, 2004 , and in revised form, January 13, 2005.

^* This work was supported in part by National Institutes of Health NHLBI Grant PO1 HL66105 (to H. F. L.) and American Heart Association Grant 0151215T (to C. C. D.). 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.

Supported in part by a National Research Service Award postdoctoral research fellowship.

To whom correspondence should be addressed: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142. Tel.: 617-258-5216; Fax: 617-258-6768; E-mail: lodish{at}wi.mit.edu.

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