PPAR-alpha dependent regulation of vanin-1 mediates hepatic lipid metabolism

JOURNAL OF HEPATOLOGY

卷:61

Article

van Diepen, Janna A.¹  Jansen, Patrick A.²  Ballak, Dov B.¹  Hijmans, Anneke¹  Hooiveld, Guido J.³  Rommelaere, Samuel^4,5,6  Galland, Franck^4,5,6  Naquet, Philippe^4,5,6  Rutjes, Floris P. J. T.⁷  Mensink, Ronald P.⁸  Schrauwen, Patrick⁸  Tack, Cees J.¹  Netea, Mihai G.¹  Kersten, Sander³  Schalkwijk, Joost²  Stienstra, Rinke^1,3 

[1] Radboud Univ Nijmegen, Med Ctr, Dept Med, NL-6525 ED Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, NL-6525 ED Nijmegen, Netherlands

[3] Wageningen Univ, Div Human Nutr, Nutr Metab & Genom Grp, NL-6700 AP Wageningen, Netherlands

[4] Aix Marseille Univ, UM2, CIML, Marseille, France

[5] INSERM, U1104, F-13258 Marseille, France

[6] CNRS, UMR7280, Marseille, France

[7] Radboud Univ Nijmegen, Inst Mol & Mat, Dept Synthet Organ Chem, NL-6525 ED Nijmegen, Netherlands

[8] Maastricht Univ, Med Ctr, NUTRIM Sch Nutr Toxicol & Metab, Dept Human Biol, Maastricht, Netherlands

关键词: Peroxisome proliferator-activated receptor alpha alpha;    PPAR;    Vanin;    Pantetheinase;    Lipid;    Fasting;    Steatosis;    Triglyceride;    Fenofibrate;   

DOI  :  10.1016/j.jhep.2014.04.013

来源: Elsevier

【 摘 要 】

Background & Aims: Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a key regulator of hepatic fat oxidation that serves as an energy source during starvation. Vanin-1 has been described as a putative PPAR alpha 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 PPAR alpha 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 PPAR alpha activity. In addition, activation of mouse PPAR alpha regulates hepatic- and plasma vanin activity. In humans, consistent with regulation by PPAR alpha, plasma vanin activity increases in all subjects after prolonged fasting, as well as after treatment with the PPAR alpha 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 PPAR alpha and that plasma vanin activity could serve as a readout of changes in PPAR alpha activity in human subjects. In addition, our data propose a role for vanin-1 in regulation of hepatic TG levels during fasting. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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