The role and regulation of the peroxisome proliferator activated receptor alpha in human liver

Abstract

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand-activated transcription factor that is abundantly expressed in liver. PPARalpha is activated by fatty acids and various other lipid species, as well as by a class of chemicals referred to as peroxisome proliferators. Studies in mice have shown that PPARalpha serves as the master regulator of hepatic lipid metabolism during fasting. In addition, PPARalpha suppresses inflammation and the acute phase response. Comparatively little is known about PPARalpha in human liver. Here, an overview is provided of the role and regulation of PPARalpha in human liver. The main outcomes are: 1) the level of PPARA mRNA expression in human and mouse liver is similar. 2) Expression of PPARA in human liver is reduced in patients with non-alcoholic steatohepatitis or infected with the hepatitis C virus. 3) PPARalpha in human liver is able to effectively induce the expression of numerous genes involved in numerous lipid metabolic pathways, including microsomal, peroxisomal and mitochondrial fatty acid oxidation, fatty acid binding and activation, fatty acid elongation and desaturation, synthesis and breakdown of triglycerides and lipid droplets, lipoprotein metabolism, gluconeogenesis, bile acid metabolism, and various other metabolic pathways and genes. 4) PPARalpha activation in human liver causes the down-regulation of a large number of genes involved in various immunity-related pathways. 5) Peroxisome proliferators do not promote tumour formation in human liver as opposed to mouse liver because of structural and functional differences between human and mouse PPARalpha. 6) In addition to helping to correct dyslipidemia, PPARalpha agonists may hold promise as a therapy for patients with cholestatic liver diseases, non-alcoholic fatty liver disease, and/or type 2 diabetes.