Exploring the activation and function of PPARa and PPARß/d using genomics

For many tissues fatty acids represent the major source of fuel. In the past few decades it has become evident that in addition to their role as energy substrates, fatty acids also have an important signaling function by modulating transcription of genes. An important group of transcription factors involved in mediating the effects of dietary fatty acids on gene transcription are the Peroxisome Proliferator-Activated Receptors (PPARs). PPARs are members of the superfamily of nuclear hormone receptors and regulate genes involved in numerous important biological processes, ranging from lipid metabolism to inflammation and wound healing. In the liver the dominant PPAR isoform has been show to be PPARα, although PPARβ/δ and PPARγ are expressed in liver as well. The aim of this thesis was to further characterize the role of PPARα and PPARβ/δ in hepatic metabolism and study their activation by fatty acids. Even though PPARα as gene regulator in liver has been well described, a complete overview of its target genes has been lacking so far. By combining several nutrigenomics tools, we succeeded in creating a comprehensive list of PPARα-regulated genes involved in lipid metabolism in liver. Additionally, by using a unique design where mice were fed synthetic triglycerides consisting of one type of fatty acid, we could distinguish between different types of dietary unsaturated fatty acids in their ability to activate PPARα. Although it is well known that PPARα plays an important role in liver during fasting, no direct in vivo evidence exists that circulating free fatty acids are able to ligand activate hepatic PPARα. In our studies, we found that upregulation of gene expression by PPARβ/δ is sensitive to circulating plasma free fatty acids whereas this is not the case for PPARα. Not much is known about the function of PPARβ/δ in the liver. In order to better understand the role of this nuclear receptor, we compared the effects of PPARα and PPARβ/δ deletion on whole genome gene regulation and plasma and liver metabolites. Our results revealed that PPARβ/δ does not mediate an adaptive response to fasting, and pointed to a role for PPARβ/δ in hepatic glucose- and lipoprotein metabolism. In conclusion, this thesis contributes to the important work of mapping the molecular mechanisms dictating lipid metabolism in the liver. By using several nutrigenomics tools, we are able to show that PPARα is a key mediator of the effect of dietary fatty acids on hepatic gene expression. In addition, we better define the roles of PPARα and PPARβ/δ in hepatic metabolism and provide a new concept for functional differentiation between PPARs in liver.