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J. Biol. Chem., Vol. 282, Issue 28, 20573-20583, July 13, 2007

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Fatty Acid Transport Protein 4 Is the Principal Very Long Chain Fatty Acyl-CoA Synthetase in Skin Fibroblasts^*

Zhenzhen Jia, Casey L. Moulson, Zhengtong Pei^¶, Jeffrey H. Miner^¶, and Paul A. Watkins^¶1

From the Kennedy Krieger Institute and the ^¶Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 and the Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

Fatty acid transport protein 4 (FATP4) is a fatty acyl-CoA synthetase that preferentially activates very long chain fatty acid substrates, such as C24:0, to their CoA derivatives. To gain better insight into the physiological functions of FATP4, we established dermal fibroblast cell lines from FATP4-deficient wrinkle-free mice and wild type (w.t.) mice. FATP4 -/- fibroblasts had no detectable FATP4 protein by Western blot. Compared with w.t. fibroblasts, cells lacking FATP4 had an 83% decrease in C24:0 activation. Peroxisomal degradation of C24:0 was reduced by 58%, and rates of C24:0 incorporation into major phospholipid species (54–64% decrease), triacylglycerol (64% decrease), and cholesterol esters (58% decrease) were significantly diminished. Because these lipid metabolic processes take place in different subcellular organelles, we used immunofluorescence and Western blotting of subcellular fractions to investigate the distribution of FATP4 protein and measured enzyme activity in fractions from w.t. and FATP4 -/- fibroblasts. FATP4 protein and acyl-CoA synthetase activity localized to multiple organelles, including mitochondria, peroxisomes, endoplasmic reticulum, and the mitochondria-associated membrane fraction. We conclude that in murine skin fibroblasts, FATP4 is the major enzyme producing very long chain fatty acid-CoA for lipid metabolic pathways. Although FATP4 deficiency primarily affected very long chain fatty acid metabolism, mutant fibroblasts also showed reduced uptake of a fluorescent long chain fatty acid and reduced levels of long chain polyunsaturated fatty acids. FATP4-deficient cells also contained abnormal neutral lipid droplets. These additional defects indicate that metabolic abnormalities in these cells are not limited to very long chain fatty acids.

Received for publication, January 19, 2007 , and in revised form, May 22, 2007.

^* This work was supported by National Institutes of Health Grants NS37355 (to P. A. W.), HD10981 (to P. A. W.), HD24061 (to P. A. W.), and AR49269 (to J. H. M.). 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: Kennedy Krieger Institute, 707 N. Broadway, Baltimore, MD 21205. Tel.: 443-923-2754; Fax: 443-923-2755; E-mail: watkins{at}kennedykrieger.org.

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