Genome-wide analysis of PPARα activation in murine small intestine

The peroxisome proliferator- activated receptor alpha ( PPAR alpha) is a fatty acid-activated transcription factor that governs a variety of biological processes. Little is known about the role of PPAR alpha in the small intestine. Since this organ is frequently exposed to high levels of PPAR alpha ligands via the diet, we set out to characterize the function of PPAR alpha in small intestine using functional genomics experiments and bioinformatics tools. PPAR alpha was expressed at high levels in both human and murine small intestine. Detailed analyses showed that PPAR alpha was expressed most highly in villus cells of proximal jejunum. Microarray analyses of total tissue samples revealed, that in addition to genes involved in fatty acid and triacylglycerol metabolism, transcription factors and enzymes connected to sterol and bile acid metabolism, including FXR and SREBP1, were specifically induced. In contrast, genes involved in cell cycle and differentiation, apoptosis, and host defense were repressed by PPAR alpha activation. Additional analyses showed that intestinal PPAR alpha- dependent gene regulation occurred in villus cells. Functional implications of array results were corroborated by morphometric data. The repression of genes involved in proliferation and apoptosis was accompanied by a 22% increase in villus height and a 34% increase in villus area of wild- type animals treated with WY14643. This is the first report providing a comprehensive overview of processes under control of PPAR alpha in the small intestine. We show that PPAR alpha is an important transcriptional regulator in small intestine, which may be of importance for the development of novel foods and therapies for obesity and inflammatory bowel diseases.