PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression.

The selective absorption of nutrients and other food constituents in the small intestine is mediated by a group of transport proteins and metabolic enzymes, often collectively called 'intestinal barrier proteins'. An important receptor that mediates the effects of dietary lipids on gene expression is the peroxisome proliferator-activated receptor alpha (PPARalpha), which is abundantly expressed in enterocytes. In this study we examined the effects of acute nutritional activation of PPARalpha on expression of genes encoding intestinal barrier proteins. To this end we used triacylglycerols composed of identical fatty acids in combination with gene expression profiling in wild-type and PPARalpha-null mice. Treatment with the synthetic PPARalpha agonist WY14643 served as reference. We identified 74 barrier genes that were PPARalpha-dependently regulated 6 hours after activation with WY14643. For eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and oleic acid (OA) these numbers were 46, 41, and 19, respectively. The overlap between EPA-, DHA-, and WY14643-regulated genes was considerable, whereas OA treatment showed limited overlap. Functional implications inferred form our data suggested that nutrient-activated PPARalpha regulated transporters and phase I/II metabolic enzymes were involved in a) fatty acid oxidation, b) cholesterol, glucose, and amino acid transport and metabolism, c) intestinal motility, and d) oxidative stress defense. We identified intestinal barrier genes that were PPARalpha-dependently regulated after acute activation by fatty acids. This knowledge provides a better understanding of the impact dietary fat has on the barrier function of the gut, identifies PPARalpha as an important factor controlling this key function, and underscores the importance of PPARalpha for nutrient-mediated gene regulation in intestine.