The RNA-binding protein vigilin regulates VLDL secretion through modulation of Apob mRNA translation.
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.
Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern Weg 7, 8093 Zurich, Switzerland.
Mehrpouya B
MB
Mobin
Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.
Stefanie
S
Gerstberger
Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, Marchioninistr. 15, 81377 Munich, Germany.
Daniel
D
Teupser
Department of Biomedicine and Clinic for Gastroenterology and Hepatology, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland.
Benedetta
B
Campana
Alnylam Pharmaceuticals, 300 Third Street, Cambridge, Massachusetts 02142, USA.
Klaus
K
Charisse
Department of Biomedicine and Clinic for Gastroenterology and Hepatology, University Hospital Basel, Hebelstrasse 20, 4031 Basel, Switzerland.
Markus H
MH
Heim
Alnylam Pharmaceuticals, 300 Third Street, Cambridge, Massachusetts 02142, USA.
Muthiah
M
Manoharan
Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.
Thomas
T
Tuschl
Institute of Molecular Health Sciences, ETH Zurich, Otto-Stern Weg 7, 8093 Zurich, Switzerland.
Markus
M
Stoffel
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