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

Peroxisome proliferator-activated receptor alpha (PPAR alpha) 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 PPAR alpha colocalize in the nucleus of mouse primary hepatocytes. Furthermore, we demonstrate by pull-down assay and immunocoprecipitation that L-FABP interacts directly with PPAR alpha. In a cell biological approach with the aid of a mammalian two-hybrid system, we provide evidence that L-FABP interacts with PPAR alpha and PPAR gamma but not with PPAR beta and retinoid X receptor-alpha 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 PPAR alpha 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 PPAR alpha 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.