A role for hepatic leptin signaling in lipid metabolism via altered very low density lipoprotein composition and liver lipase activity in mice

Authors

  • Frank K. Huynh,

    1. Departments of Cellular and Physiological SciencesUniversity of British Columbia, Vancouver, British Columbia, Canada
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  • Ursula H. Neumann,

    1. Departments of Cellular and Physiological SciencesUniversity of British Columbia, Vancouver, British Columbia, Canada
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  • Ying Wang,

    1. Departments of Molecular and Cellular Pharmacology Group, Faculty of Pharmaceutical SciencesUniversity of British Columbia, Vancouver, British Columbia, Canada
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  • Brian Rodrigues,

    1. Departments of Molecular and Cellular Pharmacology Group, Faculty of Pharmaceutical SciencesUniversity of British Columbia, Vancouver, British Columbia, Canada
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  • Timothy J. Kieffer,

    Corresponding author
    1. Departments of Cellular and Physiological SciencesUniversity of British Columbia, Vancouver, British Columbia, Canada
    2. Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
    • Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3
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    • fax: 604-822-2316;

  • Scott D. Covey

    Corresponding author
    1. Departments of Biochemistry and Molecular Biology, Life Sciences InstituteUniversity of British Columbia, Vancouver, British Columbia, Canada
    • Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3
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    • fax: 604-822-5227.


  • Potential conflict of interest: Nothing to report.

  • Supported by a grant from the Canadian Institutes of Health Research. T. J. K. received a Senior Scholarship from the Michael Smith Foundation for Health Research. F. K. H. received scholarships from the Natural Sciences and Engineering Research Council of Canada and the Canadian Diabetes Association. U. H. N. received the University of British Columbia Summer Student Research Program award sponsored by the Kinsley Brotherton McLeod Endowment and the Florence & George Heighway Endowment Fund.

Abstract

Obesity is highly associated with dyslipidemia and cardiovascular disease. However, the mechanism behind this association is not completely understood. The hormone leptin may be a molecular link between obesity and dysregulation of lipid metabolism. Leptin can affect lipid metabolism independent of its well-known effects on food intake and energy expenditure, but exactly how this occurs is ill-defined. We hypothesized that since leptin receptors are found on the liver and the liver plays an integral role in regulating lipid metabolism, leptin may affect lipid metabolism by acting directly on the liver. To test this hypothesis, we generated mice with a hepatocyte-specific loss of leptin signaling. We previously showed that these mice have increased insulin sensitivity and elevated levels of liver triglycerides compared with controls. Here, we show that mice lacking hepatic leptin signaling have decreased levels of plasma apolipoprotein B yet increased levels of very low density lipoprotein (VLDL) triglycerides, suggesting alterations in triglyceride incorporation into VLDL or abnormal lipoprotein remodeling in the plasma. Indeed, lipoprotein profiles revealed larger apolipoprotein B-containing lipoprotein particles in mice with ablated liver leptin signaling. Loss of leptin signaling in the liver was also associated with a substantial increase in lipoprotein lipase activity in the liver, which may have contributed to increased lipid droplets in the liver. Conclusion: Lack of hepatic leptin signaling results in increased lipid accumulation in the liver and larger, more triglyceride-rich VLDL particles. Collectively, these data reveal an interesting role for hepatic leptin signaling in modulating triglyceride metabolism. (HEPATOLOGY 2013)

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