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PNAS 98 (5): 2323-2328

Copyright © 2001 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / BIOCHEMISTRY

Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors α- and {gamma}-mediated gene expression via liver fatty acid binding protein: A signaling path to the nucleus

Christian Wolfrum*, Carola M. Borrmann{dagger}, Torsten Börchers{ddagger}, and Friedrich Spener*,§

*Department of Biochemistry, University of Münster, Wilhelm-Klemm-Strasse 2, 48149 Münster, Germany; {dagger}Division of Cell Biology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; and {ddagger}Institute of Chemical and Biochemical Sensor Research, Mendelstrasse 7, 48149 Münster, Germany

Accepted for publication December 26, 2000.

Received for publication February 29, 2000.

Abstract: Peroxisome proliferator-activated receptor α (PPARα) is a key regulator of lipid homeostasis in hepatocytes and target for fatty acids and hypolipidemic drugs. How these signaling molecules reach the nuclear receptor is not known; however, similarities in ligand specificity suggest the liver fatty acid binding protein (L-FABP) as a possible candidate. In localization studies using laser-scanning microscopy, we show that L-FABP and PPARα colocalize in the nucleus of mouse primary hepatocytes. Furthermore, we demonstrate by pull-down assay and immunocoprecipitation that L-FABP interacts directly with PPARα. In a cell biological approach with the aid of a mammalian two-hybrid system, we provide evidence that L-FABP interacts with PPARα and PPAR{gamma} but not with PPARβ and retinoid X receptor-α by protein–protein contacts. In addition, we demonstrate that the observed interaction of both proteins is independent of ligand binding. Final and quantitative proof for L-FABP mediation was obtained in transactivation assays upon incubation of transiently and stably transfected HepG2 cells with saturated, monounsaturated, and polyunsaturated fatty acids as well as with hypolipidemic drugs. With all ligands applied, we observed strict correlation of PPARα and PPAR{gamma} transactivation with intracellular concentrations of L-FABP. This correlation constitutes a nucleus-directed signaling by fatty acids and hypolipidemic drugs where L-FABP acts as a cytosolic gateway for these PPARα and PPAR{gamma} agonists. Thus, L-FABP and the respective PPARs could serve as targets for nutrients and drugs to affect expression of PPAR-sensitive genes.

§ To whom reprint requests should be addressed. E-mail: spener{at}uni-muenster.de.

Communicated by Tibor Farkas, Hungarian Academy of Sciences, Szeged, Hungary

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