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

Liver X receptor-α (LXRα) 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 PPARα as an intestine-specific LXR target gene. Chronic administration of LXR synthetic agonists led to a significant increase of PPARα mRNA levels in the small intestine but not in the liver. In addition, this specific PPARα 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, PPARα gene induction was completely abolished in LXR-deficient mice. Finally, th...