Intestine-specific regulation of PPARα gene transcription by liver X receptors

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