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Intestine-Specific Regulation of PPAR Gene Transcription by Liver X Receptors

Institut Pasteur de Lille (S.C., B.S., S.L.), Département d’Athérosclérose, Institut National de la Santé et de la Recherche Médicale, Unité 545, F-59019 Lille, and Faculté des Sciences Pharmaceutiques et Biologiques, Université de Lille 2, F-59006 Lille, France; GlaxoSmithKline (E.B., A.-B.B., J.-J.T., S.H., P.D.), Cardiovascular and Urogenital Center of Excellence for Drug Discovery, F-91951 Les Ulis, France; and Centre National de la Recherche Scientifique Unité Mixte de Recherche 6247-GReD (F.C., J.-M.A.L.) and Centre de Recherche en Nutrition Humaine d’Auvergne (F.C., J.-M.A.L.), Clermont Université, F-63177 Aubière, France

Address all correspondence and requests for reprints to: Philippe Delerive, Ph.D., GENFIT, 885 Avenue Eugène Avinée, 59120 Loos, France. E-mail: philippe.delerive{at}genfit.com.

Liver X receptor- (LXR) and LXRβ are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They have been identified as key players in cholesterol homeostasis and lipid and glucose metabolism as well as immune and inflammatory responses. In the small intestine, LXRs have been shown not only to regulate cholesterol absorption and excretion but also to promote high-density lipoprotein biogenesis via the ATP-binding cassette A1 signaling pathway. Here, using gene expression assays, we identified PPAR as an intestine-specific LXR target gene. Chronic administration of LXR synthetic agonists led to a significant increase of PPAR mRNA levels in the small intestine but not in the liver. In addition, this specific PPAR gene up-regulation occurred in the duodenum, jejunum, and ileum in a dose-dependent manner and translated at the protein level as demonstrated by Western blot analysis. Furthermore, PPAR gene induction was completely abolished in LXR-deficient mice. Finally, the physiological relevance of LXR-mediated PPAR up-regulation in the small intestine was assessed in PPAR-deficient mice. Administration of a synthetic LXR agonist to wild-type mice led to the induction of several PPAR target genes including PDK4 and CPT1. Those effects were completely abolished in PPAR-deficient mice, demonstrating the biological relevance of this LXR-PPAR transcriptional cascade. Taken together, these results demonstrate that PPAR is an intestine-specific LXR target gene and suggest the existence of a transcriptional cross talk between those members of the nuclear receptor superfamily.