Regulation of small intestinal transport function by fatty acids and the role of PPAR alpha

A key function of the small intestine is to form a selective barrier between the body and the environment. Potentially dangerous compounds and organisms have to be kept in the lumen, while simultaneously nutrients have to be taken up efficiently. Furthermore, the enterocyte is the first place where ingested toxic compounds are metabolized and directly excreted back into the gut lumen. The Western diet contains up to 40% of fat, mainly consisting of triacylglycerols. Unsaturated fatty acids are natural agonists for the transcription factor peroxisome proliferator- activated receptor alpha (PPARα), which among others is involved in regulation of lipid metabolism. In this thesis the effects of dietary lipids and the role of PPARα on small intestinal physiological processes was investigated, with special emphasis on nutrients, transporters and phase I/II metabolic enzymes. Therefore a nutrigenomics approach was applied using a PPARα-null mouse model. <br/> The work described in this thesis demonstrates that PPARα is highly expressed in the small intestine. We characterized the function of PPARα by treatment with the synthetic agonist WY14643 and three different triacylglycerols, which when digested are natural PPARα agonists. We found that PPARα is important in regulating transport and phase I/II metabolism genes. PPARα-dependently regulated genes of this group were especially involved in fatty acid oxidation, cholesterol, glucose, and amino acid transport and metabolism, intestinal motility, and oxidative stress. <br/> Furthermore we demonstrated that fasting induces an increased oxidation of fat and xenobiotics, increased cholesterol secretion, increased susceptibility to electrophilic stressors, and reduced intestinal motility. The role of PPARα in regulating fasting induced intestinal gene expression appeared not to be significant. <br/> Finally, we showed that small intestinal cholesterol transporters were all down-regulated after a cholesterol-free, palm-oil based high-fat diet. We showed that these effects of dietary fatty acids are LXRα- and PPARα-independent. Our results suggest that on this diet cholesterol absorption is diminished and we speculate that cholesterol efflux is reduced to spare intracellular cholesterol for chylomicron formation. <br/> Overall, the combined data from the various intervention studies clearly identified PPARα as an important transcriptional regulator in the small intestine, governing a multitude of cellular processes, including nutrient (metabolite) transport and phase I/II metabolism. However, detailed studies showed that the effects of dietary fatty acids on cholesterol uptake and metabolism are PPARα (and LXRα)-independent, demonstrating the complexity of nutrient-mediated gene expression.