title: PPAR-alpha dependent regulation of vanin-1 mediates hepatic lipid metabolism.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of hepatic fat oxidation that serves as an energy source during starvation. Vanin-1 has been described as a putative PPARα target gene in liver, but its function in hepatic lipid metabolism is unknown.
  
  
  METHODS
  We investigated the regulation of vanin-1, and total vanin activity, by PPARα in mice and humans. Furthermore, the function of vanin-1 in the development of hepatic steatosis in response to starvation was examined in Vnn1 deficient mice, and in rats treated with an inhibitor of vanin activity.
  
  
  RESULTS
  Liver microarray analyses reveals that Vnn1 is the most prominently regulated gene after modulation of PPARα activity. In addition, activation of mouse PPARα regulates hepatic- and plasma vanin activity. In humans, consistent with regulation by PPARα, plasma vanin activity increases in all subjects after prolonged fasting, as well as after treatment with the PPARα agonist fenofibrate. In mice, absence of vanin-1 exacerbates the fasting-induced increase in hepatic triglyceride levels. Similarly, inhibition of vanin activity in rats induces accumulation of hepatic triglycerides upon fasting. Microarray analysis reveal that the absence of vanin-1 associates with gene sets involved in liver steatosis, and reduces pathways involved in oxidative stress and inflammation.
  
  
  CONCLUSIONS
  We show that hepatic vanin-1 is under extremely sensitive regulation by PPARα and that plasma vanin activity could serve as a readout of changes in PPARα activity in human subjects. In addition, our data propose a role for vanin-1 in regulation of hepatic TG levels during fasting.
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Electronic address: Janna.vanDiepen@radboudumc.nl.
authors.forename: Janna A
authors.initials: JA
authors.lastname: van Diepen
authors.affiliation: Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Jansen
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Dov B
authors.initials: DB
authors.lastname: Ballak
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Anneke
authors.initials: A
authors.lastname: Hijmans
authors.affiliation: Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Hooiveld
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Rommelaere
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Galland
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Naquet
authors.affiliation: Department of Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, The Netherlands.
authors.forename: Floris P J T
authors.initials: FP
authors.lastname: Rutjes
authors.affiliation: Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Mensink
authors.affiliation: Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrauwen
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Tack
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
authors.affiliation: Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Schalkwijk
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
mesh_terms: D000581:Amidohydrolases / Q000502:physiology*; D000818:Animals; D005234:Fatty Liver / Q000209:etiology; D058851:GPI-Linked Proteins / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013217:Starvation / Q000378:metabolism
chemical_list: D058851:GPI-Linked Proteins; D047493:PPAR alpha; D000581:Amidohydrolases; C022314:pantetheinase
keywords: Fasting; Fenofibrate; Lipid; PPAR; Pantetheinase; Peroxisome proliferator-activated receptor alpha α; Steatosis; Triglyceride; Vanin