PPARα/HNF4α Interplay on Diversified Responsive Elements. Relevance in the Regulation of Liver Peroxisomal Fatty Acid Catabolism

In mammals, the liver is the major organ of fatty acid catabolism. This pathway is involved in both mitochondria and peroxisome. While mitochondria breaks down fatty acids with short, medium and long carbon chains, peroxisomes are involved in the catabolism of very long and branched chain fatty acids, which are degraded by three enzymes: acyl-CoA oxidase, multifunctional enzyme and thiolase enzyme. The active pathway results mainly from a tight transcriptional control of these gene-encoding enzymes. Two major nuclear receptors that are highly expressed in this organ are involved in this control, e. g. PPAR alpha (peroxisome proliferator-activated receptor, isoform) and HNF4 alpha (hepatic nuclear factor 4, alpha isotype). Both are key regulators of liver lipid metabolism. While numerous papers have reported on the role of PPAR in liver lipid homeostasis, less is known on the implication of HNF4 alpha in this metabolism. Moreover, very few studies have taken an interest in the important question of the implication of these two receptors and most particularly their crosstalk. This review therefore presents the current knowledge on the PPAR alpha/HNF4 alpha interplay in diversified DNA responsive elements and its relevance in the regulation fatty acid catabolism. It presents a review of the properties of the nuclear receptors PPAR alpha and HNF4 alpha, then the genes regulated by HNF4 alpha and PPAR alpha, particularly the peroxisomal enzyme target genes. To conclude, the consequences of the regulation of these genes in the liver by PPAR alpha and HNF4 alpha will be analyzed. The current data indicate the requirement of PPAR alpha and HNF4 alpha for regulation in the liver of peroxisomal and mitochondrial fatty acid beta-oxidation, cholesterol and bile acid metabolism, lipoprotein metabolism and consequently the prevention of liver steatosis. However, several questions remain unsolved. To show the interplay of PPAR alpha and HNF4 alpha in the regulation of liver fatty acid metabolism, different strategies are proposed.