The RNA-binding protein Hdlbp/Vigilin is increased in hepatic steatosis and regulates VLDL secretion through modulation of Apob mRNA translation

ABSTRACT: The liver exerts a wide range of essential functions including the synthesis of plasma proteins and the integration of glucose and lipid homeostasis. While the role of transcriptional networks in the tight regulation of these processes has been extensively studied in healthy and disease states, much less is known about post-transcriptional control of gene expression through RNA-binding proteins (RBP). Here, we report that the highly expressed and conserved RBP Hdlbp/Vigilin is upregulated in patients with non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) and in livers of insulin resistant obese mice. Gain and loss of function studies revealed that Vigilin regulates VLDL secretion through the modulation of ApoB mRNA translation. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) analysis in primary hepatocytes demonstrated that Vigilin predominantly binds to CU-rich regions in coding sequences of transcripts of further metabolically relevant secretory proteins such as Apob/apoliproteinB, Ahsg/fetuin-A, Apoc3/apolipoproteinC-III, Fn1/fibronectin, Orm1/orosomucoid and Serpina1/alpha-1-antitrypsin. While mRNA levels of these targets did not change, protein levels were substantially decreased upon knockdown of Vigilin. Hepatic long-term knockdown via GalNAc-conjugated siRNAs ameliorated elevated VLDL/LDL levels and the formation of atherosclerotic plaques in Ldlr–/– mice. These studies uncover a role for Vigilin as a key regulator of hepatic Apob translation and secretion through binding to its mRNA and demonstrate the therapeutic potential of inhibiting Vigilin for cardiovascular diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE78084 | GEO | 2017/01/01

SECONDARY ACCESSION(S): PRJNA312585

REPOSITORIES: GEO