Hepatocyte-specific Ptpn6 deletion promotes hepatic lipid accretion, but reduces NAFLD in diet-induced obesity: Potential role of PPARγ

Authors

  • Elaine Xu,

    1. Department of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada
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  • Marie-Pier Forest,

    1. Department of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada
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  • Michael Schwab,

    1. Department of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada
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  • Rita Kohen Avramoglu,

    1. Department of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada
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  • Emmanuelle St-Amand,

    1. Department of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada
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  • Annabelle Z. Caron,

    1. Department of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada
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  • Kerstin Bellmann,

    1. Department of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada
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  • Michaël Shum,

    1. Department of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada
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  • Gregory Voisin,

    1. McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada
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  • Marilene Paquet,

    1. Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, Québec, Canada
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  • Alain Montoudis,

    1. Department of Nutrition, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Québec, Canada
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  • Emile Lévy,

    1. Department of Nutrition, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Québec, Canada
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  • Katherine A. Siminovitch,

    1. Department of Medicine, University of Toronto, Mount Sinai Hospital Samuel Lunenfeld Research Institute, Toronto, ON, Canada
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  • Benjamin G. Neel,

    1. Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Hospital and Department of Medical Biophysics, University of Toronto, Ontario, Canada
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  • Nicole Beauchemin,

    1. Goodman Cancer Research Centre and Departments of Biochemistry, Medicine and Oncology, McGill University, Montréal, Québec, Canada
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  • André Marette

    Corresponding author
    1. Department of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada
    • Address reprint requests to: André Marette, Ph.D., Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Québec, Canada, G1V 4G5. E-mail: andre.marette@criucpq.ulaval.ca; fax: 418-656-4749.

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  • Potential conflict of interest: Dr. Neel consults for and owns stock in Koltan.

  • Funded by grants from the Canadian Institutes of Health Research (CIHR, FRN# 82817) to A.M., N.B. and K.S. and grant R37 CA49152 to B.G.N. A.M. holds a CIHR/Pfizer Research Chair in the pathogenesis of insulin resistance and cardiovascular diseases. K.S. is supported by a Canada Research Chair and the Sherman Family Chair in Genomic Medicine. B.G.N. is a Canada Research Chair and is also partially supported by the Ontario Ministry of Health and Long-Term Care and the Princess Margaret Hospital Foundation. E.X. received the Canadian Diabetes Association (CDA) doctoral student award and a studentship from the CIHR training program in obesity at Laval University.

Abstract

Hepatocyte-specific Shp1 knockout mice (Ptpn6H-KO) are protected from hepatic insulin resistance evoked by high-fat diet (HFD) feeding for 8 weeks. Unexpectedly, we report herein that Ptpn6H-KO mice fed an HFD for up to 16 weeks are still protected from insulin resistance, but are more prone to hepatic steatosis, as compared with their HFD-fed Ptpn6f/f counterparts. The livers from HFD-fed Ptpn6H-KO mice displayed 1) augmented lipogenesis, marked by increased expression of several hepatic genes involved in fatty acid biosynthesis, 2) elevated postprandial fatty acid uptake, and 3) significantly reduced lipid export with enhanced degradation of apolipoprotein B (ApoB). Despite more extensive hepatic steatosis, the inflammatory profile of the HFD-fed Ptpn6H-KO liver was similar (8 weeks) or even improved (16 weeks) as compared to their HFD-fed Ptpn6f/f littermates, along with reduced hepatocellular damage as revealed by serum levels of hepatic enzymes. Interestingly, comparative microarray analysis revealed a significant up-regulation of peroxisome proliferator-activated receptor gamma (PPARγ) gene expression, confirmed by quantitative polymerase chain reaction. Elevated PPARγ nuclear activity also was observed and found to be directly regulated by Shp1 in a cell-autonomous manner. Conclusion: These findings highlight a novel role for hepatocyte Shp1 in the regulation of PPARγ and hepatic lipid metabolism. Shp1 deficiency prevents the development of severe hepatic inflammation and hepatocellular damage in steatotic livers, presenting hepatocyte Shp1 as a potential novel mediator of nonalcoholic fatty liver diseases in obesity. (Hepatology 2014;59:1803–1815)

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