Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms12848
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Funding
- Boehringer Ingelheim Fonds PhD Fellowship
- European Research Council (ERC) [250210]
- National Center of Competence in Research (NCCR) on RNA Biology and Disease
- Howard Hughes Medical Institute (HHMI)
- Swiss National Science Foundation [310030B_147089/1, 310030_141209]
- NIH transformative research award [R01GM104962]
- European Research Council (ERC) [250210] Funding Source: European Research Council (ERC)
- Swiss National Science Foundation (SNF) [310030_141209] Funding Source: Swiss National Science Foundation (SNF)
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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.
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