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

摘要

pLiver fatty-acid-binding protein (L-FABP) is a cytoplasmic polypeptide that binds with strong affinity especially to long-chain fatty acids (LCFAs). It is highly expressed in both the liver and small intestine, where it is thought 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 both fibrate hypolipidaemic drugs and LCFAs, it seems to be under the control of transcription factors, termed peroxisome-proliferator-activated receptors (PPARs), activated by fibrate or FAs. However, the precise molecular mechanism by which these regulations take place remain to be fully substantiated. Using transfection assays, we found that the different PPAR subtypes (α, γ and δ) are able to mediate the up-regulation by FAs of the gene encoding L-FABP iin vitro/i. Through analysis of LCFA- and fibrate-mediated effects on L-FABP mRNA levels in wild-type and PPARα-null mice, we have found that PPARα 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 PPARδ/α agonist GW2433 is able to up-regulate the gene encoding L-FABP in the intestine of PPARα-null mice. These findings demonstrate that PPARδ can act as a fibrate/FA-activated receptor in tissues in which it is highly expressed and that L-FABP is a PPARδ target gene in the small intestine. We propose that PPARδ contributes to metabolic adaptation of the small intestine to changes in the lipid content of the diet./p