Intestine-specific regulation of PPARalpha gene transcription by liver X receptors.

Liver X receptor-alpha (LXRalpha) and LXRbeta 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 PPARalpha as an intestine-specific LXR target gene. Chronic administration of LXR synthetic agonists led to a significant increase of PPARalpha mRNA levels in the small intestine but not in the liver. In addition, this specific PPARalpha 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, PPARalpha gene induction was completely abolished in LXR-deficient mice. Finally, the physiological relevance of LXR-mediated PPARalpha up-regulation in the small intestine was assessed in PPARalpha-deficient mice. Administration of a synthetic LXR agonist to wild-type mice led to the induction of several PPARalpha target genes including PDK4 and CPT1. Those effects were completely abolished in PPARalpha-deficient mice, demonstrating the biological relevance of this LXR-PPARalpha transcriptional cascade. Taken together, these results demonstrate that PPARalpha is an intestine-specific LXR target gene and suggest the existence of a transcriptional cross talk between those members of the nuclear receptor superfamily.