title: The role and regulation of the peroxisome proliferator activated receptor alpha in human liver.
abstract: The peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that is abundantly expressed in liver. PPARα 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 PPARα serves as the master regulator of hepatic lipid metabolism during fasting. In addition, PPARα suppresses inflammation and the acute phase response. Comparatively little is known about PPARα in human liver. Here, an overview is provided of the role and regulation of PPARα 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) PPARα 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) PPARα 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 PPARα. 6) In addition to helping to correct dyslipidemia, PPARα agonists may hold promise as a therapy for patients with cholestatic liver diseases, non-alcoholic fatty liver disease, and/or type 2 diabetes.
authors.affiliation: Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, The Netherlands. Electronic address: sander.kersten@wur.nl.
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
authors.affiliation: Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, The Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
mesh_terms: D000818:Animals; D058607:Fibric Acids / Q000627:therapeutic use; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008954:Models, Biological; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000378:metabolism; D047493:PPAR alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D058607:Fibric Acids; D008024:Ligands; D047493:PPAR alpha
keywords: Human liver; Lipid metabolism; Non-alcoholic fatty liver disease; PPARα; Target genes