Apolipoprotein B100 acts as a molecular link between lipid-induced endoplasmic reticulum stress and hepatic insulin resistance

Authors

  • Qiaozhu Su,

    1. Molecular Structure and Function, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Julie Tsai,

    1. Molecular Structure and Function, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada
    2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
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  • Elaine Xu,

    1. Molecular Structure and Function, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Wei Qiu,

    1. Molecular Structure and Function, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Erika Bereczki,

    1. Institute of Biochemistry, Biological Research Center, Szeged, Hungary
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  • Miklos Santha,

    1. Institute of Biochemistry, Biological Research Center, Szeged, Hungary
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  • Khosrow Adeli

    Corresponding author
    1. Molecular Structure and Function, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada
    2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
    • Division of Clinical Biochemistry, Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8
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    • fax: 416-813-6257


  • Potential conflict of interest: Nothing to report.

Abstract

Accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER) results in ER stress and lipid overload-induced ER stress has been implicated in the development of insulin resistance. Here, evidence is provided for a molecular link between hepatic apolipoprotein B100 (apoB100), induction of ER stress, and attenuated insulin signaling. First, in vivo upregulation of hepatic apoB100 by a lipogenic diet was found to be closely associated with ER stress and attenuated insulin signaling in the liver. Direct in vivo overexpression of human apoB100 in a mouse transgenic model further supported the link between excessive apoB100 expression and hepatic ER stress. Human apoB100 transgenic mice exhibited hypertriglyceridemia and hyperglycemia. In vitro, accumulation of cellular apoB100 by free fatty acid (oleate) stimulation or constant expression of wild-type or N-glycosylation mutant apoB50 in hepatic cells induced ER stress. This led to perturbed activation of glycogen synthase kinase 3 and glycogen synthase by way of the activation of c-Jun N-terminal kinase and suppression of insulin signaling cascade, suggesting that dysregulation of apoB was sufficient to disturb ER homeostasis and induce hepatic insulin resistance. Small interfering (si)RNA-mediated attenuation of elevated apoB level in the apoB50-expressing cells rescued cells from lipid-induced ER stress and reversed insulin insensitivity. Conclusion: These findings implicate apoB100 as a molecular link between lipid-induced ER stress and hepatic insulin resistance. (HEPATOLOGY 2009.)

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