Phospholipid transfer activity of microsomal triglyceride transfer protein produces apolipoprotein B and reduces hepatosteatosis while maintaining low plasma lipids in mice

Authors

  • Irani Khatun,

    1. School of Graduate Studies, Molecular and Cellular Biology Program, SUNY Downstate Medical Center, Brooklyn, NY
    2. Departments of Cell Biology and Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY
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    • These authors contributed equally to this work.

  • Sebastian Zeissig,

    1. Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
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    • These authors contributed equally to this work.

  • Jahangir Iqbal,

    1. Departments of Cell Biology and Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY
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  • Minghui Wang,

    1. University of Alabama, Birmingham, AL
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  • David Curiel,

    1. University of Alabama, Birmingham, AL
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  • Gregory S. Shelness,

    1. Wake Forest University School of Medicine, Winston-Salem, NC
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  • Richard S. Blumberg,

    Corresponding author
    1. Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    • Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115
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    • Co-senior authors.

    • fax: 617-264-5185

  • M.Mahmood Hussain

    Corresponding author
    1. Departments of Cell Biology and Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY
    • Departments of Cell Biology and Pediatrics, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11230
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    • Co-senior authors.

    • fax: 718-270-2462


  • Potential conflict of interest: Nothing to report.

Abstract

Microsomal triglyceride transfer protein (MTP), essential for apolipoprotein B (apoB) biosynthesis, evolved as a phospholipid transfer protein and acquired triglyceride transfer activity during a transition from invertebrates to vertebrates. But it is unknown whether MTP directly transfers lipids onto apoB in vivo and, if it does, whether both neutral and polar lipid transfer activities of MTP are critical for lipoprotein assembly. The molecular bases for differences in lipid transfer activities with respect to distinct domains in Drosophila MTP (dMTP) and human MTP (hMTP) are not obvious because both proteins have very similar primary, secondary, and tertiary structures. We used an in vivo approach to delineate physiological significance of these distinct lipid transfer activities by expressing dMTP (transfers phospholipids) and hMTP (transfers phospholipids and triglycerides) orthologs using adenoviruses in liver-specific MTP-deficient (L-MTP−/−) mice that have low plasma and high hepatic lipids. Both orthologs improved plasma lipids but plasma triglycerides were lower in dMTP mice due to lower hepatic triglyceride and apoB production. Hepatosteatosis in L-MTP−/− mice was ameliorated to similar levels by both. Attenuation of hepatosteatosis upon dMTP expression pertained to enhanced β-oxidation with no changes in lipogenesis. Phospholipid transfer activity of MTP promoted biogenesis of both apoB48 and apoB100-containing very low density lipoprotein in addition to a phospholipid-rich apoB48-containing high-density lipoprotein particle. Triglyceride transfer activity augmented the biosynthesis of triglyceride-rich lipoproteins by increasing the formation of these particles in the lumen of the endoplasmic reticulum. Conclusion: Based on these findings, we posit that the selective inhibition of MTP triglyceride transfer activity might reduce hyperlipidemia while protecting liver from excess lipid accumulation. (HEPATOLOGY 2011)

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