imprint:
Springer Science and Business Media LLC, 2016
Published in:Nature Communications
Language:
English
DOI:
10.1038/ncomms12848
ISSN:
2041-1723
Origination:
Footnote:
Description:
<jats:title>Abstract</jats:title><jats:p>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<jats:italic>in vivo</jats:italic>, biochemical and genomic approaches, we demonstrate that vigilin controls very-low-density lipoprotein (VLDL) secretion through the modulation of apolipoproteinB/<jats:italic>Apob</jats:italic>mRNA translation. Crosslinking studies reveal that vigilin binds to CU-rich regions in the mRNA coding sequence of<jats:italic>Apob</jats:italic>and other proatherogenic secreted proteins, including apolipoproteinC-III/<jats:italic>Apoc3</jats:italic>and fibronectin/<jats:italic>Fn1</jats:italic>. Consequently, hepatic vigilin knockdown decreases VLDL/low-density lipoprotein (LDL) levels and formation of atherosclerotic plaques in<jats:italic>Ldlr</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>mice. These studies uncover a role for vigilin as a key regulator of hepatic<jats:italic>Apob</jats:italic>translation and demonstrate the therapeutic potential of inhibiting vigilin for cardiovascular diseases.</jats:p>