Modulation of the expression of peroxisome proliferator-activated receptor-dependent genes through disproportional expression of two subtypes in the small intestine

We have reported that dietary long-chain triacylglycerols (LCT) enhance the transcription of cellular retinol-binding protein, the type II (CRBPII) ge ne, and the liver-type fatty acid-binding protein (L-FABP) gene in the smal l intestine. Because the cis elements on the CRBPII gene consisting of two AGGTCA motifs separated by a single nucleotide are known to bind not only t he 9-cis-retinoic acid receptor (RXR) homodimer, but also the peroxisome pr oliferator-activated receptor (PPAR)-RXR heterodimer, it has been implicate d that the unsaturated long-chain fatty acids, as the ligands of the PPAR, might activate the transcription of the CRBPII gene, thereby making use of the RXR-response elements (RXRE and RE3) as the PPAR-response element (PPRE ). In this study, we found that the PPAR alpha mRNA level in the rat jejunu m was elevated by dietary fat, whereas the PPAR delta mRNA level was reduce d under this condition. Electrophoretic mobility-shift assay revealed that both PPAR alpha -RXR alpha and PPAR delta -RXR alpha heterodimers, specific ally and in a dose-dependent manner, bound to the two PPRE-like elements of the rat CRBPII gene as well as the known PPREs in the L-FABP and acyl-CoA oxidase genes. The binding of the PPAR alpha -RXR alpha heterodimer to the CRBPII-RXRE, the CRBPII-RE3, and the PPREs of L-FABP, HMG-CoA synthase, and acyl-CoA oxidase was gradually diminished by the addition of increasing am ounts of PPAR delta. The binding of the PPAR delta -RXR alpha heterodimer t o CRBPII-RXRE, CRBPII- RE3, and other PPREs was also gradually reduced by t he addition of increasing amounts of PPAR alpha. Using Escherichia coli-exp ressed RXR alpha, we showed that the mutual competition for RXR alpha with PPAR alpha and PPAR delta occurred at the protein level. These results sugg est that the transcriptions of CRBPII, L-FABP, and the other PPAR-dependent genes in the small intestine may be coordinately regulated by the dispropo rtional expression of PPAR alpha and PPAR delta. (C) 2001 Academic Press.