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

Mehrpouya B. Mobin, Stefanie Gerstberger, Daniel Teupser, Benedetta Campana, Klaus Charisse, Markus H. Heim, Muthiah Manoharan, Thomas Tuschl and Markus Stoffel ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12848

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