Transcriptional regulation of nutrient metabolism by PPARa,y and LXRa

Peroxisome Proliferators Activated Receptors (PPARs) and Liver X Receptors (LXRs) are Nuclear Hormones Receptors that mediate the effect of nutrients on gene expression by acting as sensors for fatty acids and cholesterol-derived metabolites, respectively. In as much as metabolic diseases evolve by unfavorable genetics in combination with excess exposure to nutrients, investigation into the mode of action of PPARs and LXRs may provide important new leads for the pharmacological treatment of these diseases.The work presented in this PhD thesis demonstrates that PPARadirectly stimulates the hepatic conversion of glycerol into glucose, which was the first report showing that PPARadirectly governs hepatic gluconeogenesis. Regulation of gluconeogenesis by PPARalikely explains why PPARanull mice develop severe hypoglycemia when fasted. This function of PPARaappears to be conserved and functional in human since activation of PPARawith synthetic PPARaligand decreased the plasma glycerol levels.In the second part of this PhD thesis work it is demonstrated that PPARabecomes activated in liver upon high fat diet and associated insulin resistance. Although activation of PPARaby high fat feeding was weak relative to treatment with synthetic PPARaagonist or fasting, consistent upregulation of PPARatarget genes was observed that became evident after comprehensive expression profiling by micro-array. The results obtained illustrate the power of a focused nutrigenomics approach to promote our understanding of regulation of gene expression by nutrients and their specific role in governing nutrient metabolism.In the last part of the manuscript we describe novel cross-talk between PPARg, LXRaand their heterodimeric partner RXR in adipose tissue. We show that LXRaand its ligand T0901317 specifically repress the expression of cGPDH in vivo and in differentiated mature adipocytes. Further investigation of the molecular mechanism demonstrated that liganded LXRaprevents the binding of PPARgto the PPREs of the cGPDH promoter by competing with PPARgfor their reciprocal partner RXR. Our data reveal novel cross-talk between PPARg, LXRaand RXR in the control of gene expression in adipocytes.