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J. Biol. Chem., Vol. 278, Issue 48, 47636-47643, November 28, 2003

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Fatty Acid-binding Protein-Hormone-sensitive Lipase Interaction

FATTY ACID DEPENDENCE ON BINDING^*

Anne E. Jenkins-Kruchten, Assumpta Bennaars-Eiden¶, James R. Ross, Wen-Jun Shen||**, Fredric B. Kraemer||**, and David A. Bernlohr

From the Departments of Biochemistry, Molecular Biology, and Biophysics, The University of Minnesota, Minneapolis, Minnesota 55455, the ^||Division of Endocrinology, Department of Medicine, Stanford University, Stanford, California 94305, and the ^**Veterans Administration Palo Alto Health Care System, Palo Alto, California 94304

Adipose lipolysis is mediated, in part, via interaction of fatty acid-binding protein (FABP) with hormone-sensitive lipase (HSL). Mice with reduced FABP content in fat (adipocyte FABP null) exhibit diminished fat cell lipolysis, whereas transgenic mice with increased FABP content in fat (epithelial FABP transgenic) exhibit enhanced lipolysis. To examine the relationship between the binding of FABP to HSL and activation of catalytic activity, isothermal titration microcalorimetry as well as kinetic analysis using a variety of FABP isoforms have been employed. In the absence of fatty acids, no FABP-HSL association could be demonstrated for any FABP form. However, in the presence of 10 µM oleate, A-FABP and E-FABP each bound to HSL with high affinity (K_d of 0.5 and 3 nM, respectively) in a 1:1 molar stoichiometry, whereas liver FABP and intestinal FABP did not exhibit any association. To compare binding to catalysis, each FABP isoform was incubated with HSL in vitro, and enzymatic activity was assessed. Importantly, each FABP form stimulated HSL activity 2-fold using cholesteryl oleate as substrate but exhibited no activation using p-nitrophenyl butyrate. The activation by A-FABP was dependent upon its fatty acid binding properties because a non-fatty acid binding mutant, R126Q, failed to activate HSL. These results suggest that binding and activation of HSL by FABPs are separate and distinct functions and that HSL contains a site for fatty acid binding that allows for FABP association.

Received for publication, July 16, 2003 , and in revised form, September 15, 2003.

^* This work was supported by National Institutes of Health Grants DK 53189 (to D. A. B.) and DK 46942 and the Research Services of the Department of Veterans Affairs (to F. B. K.). 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.

These authors contributed equally to this work.

^¶ Supported by NHLBI, National Institutes of Health Grant T32-HL07741.

To whom correspondence should be addressed: Dept. of Biochemistry, Molecular Biology, and Biophysics, The University of Minnesota, 321 Church St. SE, Minneapolis, MN 55455. Tel.: 612-624-2712; Fax: 612-625-2163; E-mail: bernl001{at}umn.edu.

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