Lipid-binding proteins modulate ligand-dependent trans-activation by peroxisome proliferator-activated receptors and localize to the nucleus as well as the cytoplasm

Peroxisome proliferator-activated receptors (PPARs) are activated by a vari ety of fatty acids, eicosanoids, and hypolipidemic and insulin-sensitizing drugs. Many of these compounds bind avidly to members of a family of small lipid-binding proteins, the fatty acid-binding proteins (FABPs), Fatty acid s are activated to CoA esters, which bind with high affinity to the acyl-Co A-binding protein (ACBP), Thus, the availability of known and potential PPA R ligands may be regulated by Lipid-binding proteins. In this report we sho w by transient transfection of CV-1 cells that coexpression of ACBP and adi pocyte lipid-binding protein (ALBP) exerts a ligand- and PPAR subtype-speci fic attenuation of PPAR-mediated transactivation, suggesting that Lipid-bin ding proteins, when expressed at high levels, may function as negative regu lators of PPAR activation by certain ligands, Expression of ACBP, ALBP, and keratinocyte lipid-binding protein (KLBP) is induced during adipocyte diff erentiation, a process during which PPAR gamma plays a prominent role. We p resent evidence that endogenous ACBP, ALBP, and KLBP not only localize to t he cytoplasm but also exhibit a prominent nuclear localization in 3T3-L1 ad ipocytes. In addition, forced expression of ACBP, ALBP, and KLBP in CV-1 ce lls resulted in a substantial accumulation of all three proteins in the nuc leus. These results suggest that lipid-binding proteins, contrary to the ge neral assumption, may exert their action in the nucleus as well as in the c ytoplasm.