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). 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 (alpha, 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-mediated effects on L-FABP mRNA levels in wild-type and PPARalpha-null mice, we have found that PPARalpha 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 PPARdelta/alpha agonist GW2433 is able to up-regulate the gene encoding L-FABP in the intestine of PPARalpha-null mice. These findings demonstrate that PPARdelta can act as a fibrate/FA-activated receptor in tissues in which it is highly expressed and that L-FABP is a PPARdelta target gene in the small intestine. We propose that PPARdelta contributes to metabolic adaptation of the small intestine to changes in the lipid content of the diet.
Poirier
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Physiologie de la Nutrition, Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation (ENSBANA) FRE 2049 CNRS, 1 Esplanade Erasme, CESG/Université de Bourgogne, F-21000 Dijon, France.
Niot
I
I
Monnot
M C
MC
Braissant
O
O
Meunier-Durmort
C
C
Costet
P
P
Pineau
T
T
Wahli
W
W
Willson
T M
TM
Besnard
P
P
D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics*; D017931:DNA Primers; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D000960:Hypolipidemic Agents; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D019787:Linoleic Acid / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010671:Phenylurea Compounds / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000502:physiology*; D014157:Transcription Factors / Q000819:agonists / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology
D002087:Butyrates; D002352:Carrier Proteins; D017931:DNA Primers; C493320:Fabp1 protein, mouse; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; C110636:GW 2433; D000960:Hypolipidemic Agents; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010671:Phenylurea Compounds; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019787:Linoleic Acid; D001629:Bezafibrate