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.