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J. Biol. Chem., Vol. 283, Issue 20, 13578-13585, May 16, 2008

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Opposite Regulation of CD36 Ubiquitination by Fatty Acids and Insulin

EFFECTS ON FATTY ACID UPTAKE^*

Jill Smith¹, Xiong Su¹, Raafat El-Maghrabi^¶, Philip D. Stahl, and Nada A. Abumrad²

From the Department of Medicine, Center for Human Nutrition, and Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, Missouri 63110 and the ^¶Department of Physiology and Biophysics, State University of New York, Stony Brook, New York 11794

FAT/CD36 is a membrane scavenger receptor that facilitates long chain fatty acid uptake by muscle. Acute increases in membrane CD36 and fatty acid uptake have been reported in response to insulin and contraction. In this study we have explored protein ubiquitination as one potential mechanism for the regulation of CD36 level. CD36 expressed in Chinese hamster ovary (CHO) or HEK 293 cells was found to be polyubiquitinated via a process involving both lysines 48 and 63 of ubiquitin. Using CHO cells expressing the insulin receptor (CHO/hIR) and CD36, it is shown that addition of insulin (100 nM, 10 and 30 min) significantly reduced CD36 ubiquitination. In contrast, ubiquitination was strongly enhanced by fatty acids (200 µM palmitate or oleate, 2 h). Similarly, endogenous CD36 in C2C12 myotubes was ubiquitinated, and this was enhanced by oleic acid treatment, which also reduced total CD36 protein in cell lysates. Insulin reduced CD36 ubiquitination, increased CD36 protein, and inhibited the opposite effects of fatty acids on both parameters. These changes were paralleled by changes in fatty acid uptake, which could be blocked by the CD36 inhibitor sulfosuccinimidyl oleate. Mutation of the two lysine residues in the carboxyl-terminal tail of CD36 markedly attenuated ubiquitination of the protein expressed in CHO cells and was associated with increased CD36 level and enhanced oleate uptake and incorporation into triglycerides. In conclusion, fatty acids and insulin induce opposite alterations in CD36 ubiquitination, modulating CD36 level and fatty acid uptake. Altered CD36 turnover may contribute to abnormal fatty acid uptake in the insulin-resistant muscle.

Received for publication, January 2, 2008 , and in revised form, March 18, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01DK 33301 (to N. A.) and 2R01GM42259 (to P. S.), Clinical Nutrition Research Unit Grant DK56351, and NHLBI Cardiovascular System: Function, Regulation, Pharmacology Training Grant T32 HL-007275 (to J. S.). This work was also supported by the Human Center for Nutrition, Washington University (to X. S.). 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 These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO 63110. Tel.: 314-747-0348; Fax: 314-362-8230; E-mail: nabumrad{at}im.wustl.edu.

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