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The RNA-binding protein vigilin regulates VLDL secretion through modulation of Apob mRNA translation

Author

Listed:
  • Mehrpouya B. Mobin

    (Institute of Molecular Health Sciences, ETH Zurich)

  • Stefanie Gerstberger

    (Howard Hughes Medical Institute, The Rockefeller University)

  • Daniel Teupser

    (Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich)

  • Benedetta Campana

    (University Hospital Basel)

  • Klaus Charisse

    (Alnylam Pharmaceuticals)

  • Markus H. Heim

    (University Hospital Basel)

  • Muthiah Manoharan

    (Alnylam Pharmaceuticals)

  • Thomas Tuschl

    (Howard Hughes Medical Institute, The Rockefeller University)

  • Markus Stoffel

    (Institute of Molecular Health Sciences, ETH Zurich)

Abstract

The liver is essential for the synthesis of plasma proteins and integration of lipid metabolism. While the role of transcriptional networks in these processes is increasingly understood, less is known about post-transcriptional control of gene expression by RNA-binding proteins (RBPs). Here, we show that the RBP vigilin is upregulated in livers of obese mice and in patients with fatty liver disease. By using in vivo, biochemical and genomic approaches, we demonstrate that vigilin controls very-low-density lipoprotein (VLDL) secretion through the modulation of apolipoproteinB/Apob mRNA translation. Crosslinking studies reveal that vigilin binds to CU-rich regions in the mRNA coding sequence of Apob and other proatherogenic secreted proteins, including apolipoproteinC-III/Apoc3 and fibronectin/Fn1. Consequently, hepatic vigilin knockdown decreases VLDL/low-density lipoprotein (LDL) levels and formation of atherosclerotic plaques in Ldlr−/− mice. These studies uncover a role for vigilin as a key regulator of hepatic Apob translation and demonstrate the therapeutic potential of inhibiting vigilin for cardiovascular diseases.

Suggested Citation

  • Mehrpouya B. Mobin & Stefanie Gerstberger & Daniel Teupser & Benedetta Campana & Klaus Charisse & Markus H. Heim & Muthiah Manoharan & Thomas Tuschl & Markus Stoffel, 2016. "The RNA-binding protein vigilin regulates VLDL secretion through modulation of Apob mRNA translation," Nature Communications, Nature, vol. 7(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12848
    DOI: 10.1038/ncomms12848
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    Cited by:

    1. Ulrike Zinnall & Miha Milek & Igor Minia & Carlos H. Vieira-Vieira & Simon Müller & Guido Mastrobuoni & Orsalia-Georgia Hazapis & Simone Giudice & David Schwefel & Nadine Bley & Franka Voigt & Jeffrey, 2022. "HDLBP binds ER-targeted mRNAs by multivalent interactions to promote protein synthesis of transmembrane and secreted proteins," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

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