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J. Biol. Chem., Vol. 281, Issue 45, 34341-34348, November 10, 2006

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Functional Compensation for Adipose Differentiation-related Protein (ADFP) by Tip47 in an ADFP Null Embryonic Cell Line^*

Carole Sztalryd¹, Ming Bell, Xinyue Lu², Pamela Mertz, Sabrina Hickenbottom, Benny H.-J. Chang^¶, Lawrence Chan^¶, Alan R. Kimmel, and Constantine Londos

From the Geriatric Research, Education and Clinical Center, Baltimore Veterans Affairs Health Care Center, Department of Medicine, School of Medicine, University of Maryland, Baltimore, Maryland 21201, the Laboratory of Cellular and Developmental Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-8028, and the ^¶Departments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, Texas 77030

Ectopic accumulation of lipid droplets in non-adipose tissues correlates with the degree of insulin resistance in these tissues. Emerging evidence indicates that lipid droplets are specialized organelles that participate in lipid metabolism and intracellular trafficking. These properties are thought to derive from the lipid droplet-associated PAT protein family (perilipin, ADFP, and Tip47). The functions of the ubiquitously distributed adipose differentiation-related protein (ADFP) and Tip47 remain unknown. To evaluate the roles of ADFP and Tip47 in lipid biogenesis and metabolism, ADFP null and wild type (wt) clonal cell lines were established from ADFP null and wt mice, respectively. In ADFP null cells, Tip47 was identified as the sole lipid droplet-associated protein from the PAT family by mass spectroscopy, which was further confirmed by immunoblotting and immunocytochemistry. Following incubation with oleic acid, ADFP null cells were able to form lipid droplets to the same extent as wt cells. No statistical differences between the two cell types were observed in NEFA uptake or lipolysis. Small interference RNAs (siRNAs) against Tip47 were found to down-regulate protein levels for Tip47 by 85%. ADFP null cells treated with Tip47 siRNA retained the ability to form lipid droplets but to a lesser extent and shunted the utilization of exogenously added NEFA from triglycerides to phospholipids. These data support the hypothesis that Tip47 plays an important role in lipid metabolism. Tip47 and ADFP in peripheral tissues may play a critical role in regulating the formation and turnover, and hence metabolic consequences, of ectopic fat.

Received for publication, March 16, 2006 , and in revised form, September 11, 2006.

^* This work was supported by Carrier Development Award 1-05-CD-17 from the American Diabetes Association (to C. S.), by the Intramural Research Program of NIDDK, National Institutes of Health (NIH). This work was also supported in part by a pilot grant from NIH Digestive Disease Center Grant DK56338 (to B. H.-J. C.) and by NIH Grant HL51586 and a grant from the TTWFC Global Foundation (to L. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-4 and Tables 1 and 2.

² Present addresses: Military Casualty Research, Walter Reed Army Institute of Research, Silver Spring, MD 20910 and the Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.

¹ To whom correspondence should be addressed: GRECC/geriatrics, Veterans Affairs Medical Center, 10 North Greene St., Baltimore, MD 21201. Tel.: 410-605-7000 5417; Fax: 410-605-7913; E-mail: csztalry{at}grecc.umaryland.edu.

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