Differential involvement of peroxisome-proliferator-activated receptors alpha and delta in fibrate and fatty-acid-mediated inductions of the gene encoding liver fatty-acid-binding protein in the liver and the small intestine

Liver fatty-acid-binding protein (L-FABP) is a cytoplasmic polypeptide that binds with strong affinity especially to long-chain fatty acids (LCFAs), I t is highly expressed in both the liver and small intestine, where it is th ought to have an essential role in the control of the cellular fatty acid ( FA) flux, Because expression of the gene encoding L-FABP is increased by bo th fibrate hypolipidaemic drugs and LCFAs, it seems to be under the control of transcription factors, termed peroxisome-proliferator-activated recepto rs (PPARs), activated by fibrate or FAs. However, the precise molecular mec hanism by which these regulations take place remain to be fully substantiat ed, Using transfection assays, we found that the different PPAR subtypes (a lpha, gamma and delta) are able to mediate the up-regulation by FAs of the gene encoding L-FABP in vitro. Through analysis of LCFA- and fibrate-mediat ed effects on L-FABP mRNA levels in wild-type and PPAR alpha -null mice, we have found that PPAR alpha in the intestine does not constitute a dominant regulator of L-FABP gene expression, in contrast with what is known in the liver, Only the PPAR delta/alpha agonist GW2433 is able to up-regulate the gene encoding L-FABP in the intestine of PPAR alpha -null mice, These find ings demonstrate that PPARB can act as a fibrate/FA-activated receptor in t issues in which it is highly expressed and that L-FABP is a PPAR delta targ et gene in the small intestine, We propose that PPAR delta contributes to m etabolic adaptation of the small intestine to changes in the lipid content of the diet.