Janna A van Diepen1, Patrick A Jansen2, Dov B Ballak3, Anneke Hijmans3, Guido J Hooiveld4, Samuel Rommelaere5, Franck Galland5, Philippe Naquet5, Floris P J T Rutjes6, Ronald P Mensink7, Patrick Schrauwen7, Cees J Tack3, Mihai G Netea3, Sander Kersten4, Joost Schalkwijk2, Rinke Stienstra8. 1. Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Electronic address: Janna.vanDiepen@radboudumc.nl. 2. Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 3. Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 4. Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands. 5. 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. 6. Department of Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, The Netherlands. 7. Department of Human Biology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands. 8. 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.
Abstract
BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: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: Mariana Verdelho Machado; Leandi Kruger; Mark L Jewell; Gregory Alexander Michelotti; Thiago de Almeida Pereira; Guanhua Xie; Cynthia A Moylan; Anna Mae Diehl Journal: Dig Dis Sci Date: 2015-09-24 Impact factor: 3.199
Authors: Janna A van Diepen; Patrick A Jansen; Dov B Ballak; Anneke Hijmans; Floris P J T Rutjes; Cees J Tack; Mihai G Netea; Joost Schalkwijk; Rinke Stienstra Journal: Sci Rep Date: 2016-03-02 Impact factor: 4.379