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Cited by 55RNA Research and SplicingCholesterol and Lipid MetabolismLipid metabolism and disorders

The RNA-binding protein vigilin regulates VLDL secretion through modulation of Apob mRNA translation

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Mobin, Mehrpouya B., Gerstberger, Stefanie, Teupser, Daniel, Campana, Benedetta, Charisse, Klaus, Heim, Markus H., Manoharan, Muthiah, Tuschl, Thomas +1 more·2016·Nature Communications
DOI 10.1038/ncomms12848PMC PMC5052685
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Abstract

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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  • HDLBP is a candidate with known effects on secretory processes including VLDL secretion.

    “A promising target from this analysis was high density lipoprotein binding protein (HDLBP), a candidate with known effects on secretory processes including VLDL secretion (14, 15).”

    From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [14]

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References 66 · Cited by 55

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  1. McKnight G. L. et al. Cloning and expression of a cellular high density lipoprotein-binding protein that is up-regulated by cholesterol loading of cells. J. Biol. Chem. 267, 12131– 12141 (1992). 1318310
  2. Schmidt C. et al. Complete cDNA sequence of chicken vigilin, a novel protein with amplified and evolutionary conserved domains. Eur. J. Biochem. 206, 625– 634 (1992). 1606952
  3. Burd C. G. & Dreyfuss G. Conserved structures and diversity of functions of RNA-binding proteins. Science 265, 615– 621 (1994). 8036511
  4. Dejgaard K. & Leffers H. Characterisation of the nucleic-acid-binding activity of KH domains. Different properties of different domains. Eur. J. Biochem. 241, 425– 431 (1996). 8917439
  5. Dodson R. E. & Shapiro D. J. Vigilin, a ubiquitous protein with 14 K homology domains, is the estrogen-inducible vitellogenin mRNA 3'-untranslated region-binding protein. J. Biol. Chem. 272, 12249– 12252 (1997). 9139664
  6. Kruse C. et al. Evidence for a novel cytoplasmic tRNA-protein complex containing the KH-multidomain protein vigilin. Biochem. J. 320, (Pt 1): 247– 252 (1996). 8947494 PMC1217924
  7. Weber V. et al. Purification and nucleic-acid-binding properties of a Saccharomyces cerevisiae protein involved in the control of ploidy. Eur. J. Biochem. 249, 309– 317 (1997). 9363784
  8. Cortés A. et al. DDP1, a single-stranded nucleic acid-binding protein of Drosophila, associates with pericentric heterochromatin and is functionally homologous to the yeast Scp160p, which is involved in the control of cell ploidy. EMBO J. 18, 3820– 3833 (1999). 10393197 PMC1171459
  9. Chen J.-Y., Chen J.-C. & Wu J.-L. Molecular cloning and functional analysis of zebrafish high-density lipoprotein-binding protein. Comp. Biochem. Physiol. B, Biochem. Mol. Biol. 136, 117– 130 (2003). 12941645
  10. Brykailo M. A., Corbett A. H. & Fridovich-Keil J. L. Functional overlap between conserved and diverged KH domains in Saccharomyces cerevisiae SCP160. Nucleic Acids Res. 35, 1108– 1118 (2007). 17264125 PMC1994781
  11. Molyneux S. D. et al. Human somatic cell mutagenesis creates genetically tractable sarcomas. Nat. Genet. 46, 964– 972 (2014). 25129143
  12. Yang W. L. et al. Vigilin is overexpressed in hepatocellular carcinoma and is required for HCC cell proliferation and tumor growth. Oncol. Rep. 31, 2328– 2334 (2014). 24676454
  13. Hirschmann W. D. et al. Scp160p is required for translational efficiency of codon-optimized mRNAs in yeast. Nucleic Acids Res. 42, 4043– 4055 (2014). 24445806 PMC3973333
  14. Mendelsohn B. A. et al. Genetic and biochemical interactions between SCP160 and EAP1 in yeast. Nucleic Acids Res. 31, 5838– 5847 (2003). 14530432 PMC219487
  15. Wang Q., Zhang Z., Blackwell K. & Carmichael G. G. Vigilins bind to promiscuously A-to-I-edited RNAs and are involved in the formation of heterochromatin. Curr. Biol. 15, 384– 391 (2005). 15723802
  16. Wintersberger U., Kühne C. & Karwan A. Scp160p, a new yeast protein associated with the nuclear membrane and the endoplasmic reticulum, is necessary for maintenance of exact ploidy. Yeast 11, 929– 944 (1995). 8533468
  17. Huertas D., Cortés A., Casanova J. & Azorín F. Drosophila DDP1, a multi-KH-domain protein, contributes to centromeric silencing and chromosome segregation. Curr. Biol. 14, 1611– 1620 (2004). 15380062
  18. Kruse C. et al. Export and transport of tRNA are coupled to a multi-protein complex. Biochem. J. 346, (Pt 1): 107– 115 (2000). 10657246 PMC1220829
  19. Gelin-Licht R., Paliwal S., Conlon P., Levchenko A. & Gerst J. E. Scp160-dependent mRNA trafficking mediates pheromone gradient sensing and chemotropism in yeast. Cell Rep. 1, 483– 494 (2012). 22832273 PMC3406329
  20. Baum S., Bittins M., Frey S. & Seedorf M. Asc1p, a WD40-domain containing adaptor protein, is required for the interaction of the RNA-binding protein Scp160p with polysomes. Biochem. J. 380, 823– 830 (2004). 15012629 PMC1224212
  21. Frey S., Pool M. & Seedorf M. Scp160p, an RNA-binding, polysome-associated protein, localizes to the endoplasmic reticulum of Saccharomyces cerevisiae in a microtubule-dependent manner. J. Biol. Chem. 276, 15905– 15912 (2001). 11278502
  22. Lang B. D. & Fridovich-Keil J. L. Scp160p, a multiple KH-domain protein, is a component of mRNP complexes in yeast. Nucleic Acids Res. 28, 1576– 1584 (2000). 10710424 PMC102792
  23. Hafner M. et al. Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141, 129– 141 (2010). 20371350 PMC2861495
  24. Corcoran D. L. et al. PARalyzer: definition of RNA binding sites from PAR-CLIP short-read sequence data. Genome Biol. 12, R79 (2011). 21851591 PMC3302668
  25. Cunningham K. S., Dodson R. E., Nagel M. A., Shapiro D. J. & Schoenberg D. R. Vigilin binding selectively inhibits cleavage of the vitellogenin mRNA 3'-untranslated region by the mRNA endonuclease polysomal ribonuclease 1. Proc. Natl Acad. Sci. USA 97, 12498– 12502 (2000). 11050168 PMC18792
  26. Woo H.-H. et al. Posttranscriptional suppression of proto-oncogene c-fms expression by vigilin in breast cancer. Mol. Cell Biol. 31, 215– 225 (2011). 20974809 PMC3019847
  27. Moretti F. A. et al. A major fraction of fibronectin present in the extracellular matrix of tissues is plasma-derived. J. Biol. Chem. 282, 28057– 28062 (2007). 17644525
  28. Ren J. et al. Long-term coronary heart disease risk associated with very-low-density lipoprotein cholesterol in Chinese: the results of a 15-Year Chinese Multi-Provincial Cohort Study (CMCS). Atherosclerosis 211, 327– 332 (2010). 20223457
  29. Schäfer C. et al. The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J. Clin. Invest. 112, 357– 366 (2003). 12897203 PMC166290
  30. Auberger P. et al. Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity. Cell 58, 631– 640 (1989). 2766355
  31. Rauth G. et al. The nucleotide and partial amino acid sequences of rat fetuin. Identity with the natural tyrosine kinase inhibitor of the rat insulin receptor. Eur. J. Biochem. 204, 523– 529 (1992). 1371750
  32. Srinivas P. R. et al. Serum alpha 2-HS-glycoprotein is an inhibitor of the human insulin receptor at the tyrosine kinase level. Mol. Endocrinol. 7, 1445– 1455 (1993). 7906861
  33. Kruse C. et al. The multi-KH protein vigilin associates with free and membrane-bound ribosomes. Cell. Mol. Life Sci. 60, 2219– 2227 (2003). 14618268 PMC11138841
  34. Rohwedder I. et al. Plasma fibronectin deficiency impedes atherosclerosis progression and fibrous cap formation. EMBO Mol. Med. 4, 564– 576 (2012). 22514136 PMC3407945
  35. Fisher E. A. et al. The triple threat to nascent apolipoprotein B. Evidence for multiple, distinct degradative pathways. J. Biol. Chem. 276, 27855– 27863 (2001). 11285257
  36. Qiu W. et al. Hepatic autophagy mediates endoplasmic reticulum stress-induced degradation of misfolded apolipoprotein B. Hepatology 53, 1515– 1525 (2011). 21360721
  37. Fisher E., Lake E. & McLeod R. S. Apolipoprotein B100 quality control and the regulation of hepatic very low density lipoprotein secretion. J. Biomed. Res. 28, 178– 193 (2014). 25013401 PMC4085555
  38. Fisher E. A. The degradation of apolipoprotein B100: multiple opportunities to regulate VLDL triglyceride production by different proteolytic pathways. Biochim. Biophys. Acta 1821, 778– 781 (2012). 22342675 PMC3593638
  39. Maczuga P. et al. Therapeutic expression of hairpins targeting apolipoprotein B100 induces phenotypic and transcriptome changes in murine liver. Gene Ther. 21, 60– 70 (2014). 24152580 PMC3881031
  40. Maeda N. et al. Targeted disruption of the apolipoprotein C-III gene in mice results in hypotriglyceridemia and protection from postprandial hypertriglyceridemia. J. Biol. Chem. 269, 23610– 23616 (1994). 8089130
  41. Westenfeld R. et al. Fetuin-A protects against atherosclerotic calcification in CKD. J. Am. Soc. Nephrol. 20, 1264– 1274 (2009). 19389852 PMC2689898
  42. Naito C. et al. Facilitatory effects of fetuin-A on atherosclerosis. Atherosclerosis 246, 344– 351 (2016). 26828753
  43. Keene J. D. RNA regulons: coordination of post-transcriptional events. Nat. Rev. Genet. 8, 533– 543 (2007). 17572691
  44. de Sousa Abreu R., Penalva L. O., Marcotte E. M. & Vogel C. Global signatures of protein and mRNA expression levels. Mol. BioSyst. 5, 1512– 1526 (2009). 20023718 PMC4089977
  45. Vogel C. et al. Sequence signatures and mRNA concentration can explain two-thirds of protein abundance variation in a human cell line. Mol. Syst. Biol. 6, 400 (2010). 20739923 PMC2947365
  46. Adiels M., Olofsson S.-O., Taskinen M.-R. & Borén J. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 28, 1225– 1236 (2008). 18565848
  47. Loria P. et al. Cardiovascular risk, lipidemic phenotype and steatosis. A comparative analysis of cirrhotic and non-cirrhotic liver disease due to varying etiology. Atherosclerosis 232, 99– 109 (2014). 24401223
  48. Teupser D., Persky A. D. & Breslow J. L. Induction of atherosclerosis by low-fat, semisynthetic diets in LDL receptor-deficient C57BL/6J and FVB/NJ mice: comparison of lesions of the aortic root, brachiocephalic artery, and whole aorta (en face measurement). Arterioscler. Thromb. Vasc. Biol. 23, 1907– 1913 (2003). 12907460
  49. Dobin A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15– 21 (2013). 23104886 PMC3530905
  50. Aalto-Setälä K. et al. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles. J. Clin. Invest. 90, 1889– 1900 (1992). 1430212 PMC443250
  51. Spitzer J. et al. PAR-CLIP (Photoactivatable Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation): a step-by-step protocol to the transcriptome-wide identification of binding sites of RNA-binding proteins. Methods Enzymol. 539, 113– 161 (2014). 24581442 PMC4180672
  52. Lawrence M. et al. Software for computing and annotating genomic ranges. PLoS Comput. Biol. 9, e1003118 (2013). 23950696 PMC3738458
  53. Robinson M. D., McCarthy D. J. & Smyth G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139– 140 (2010). 19910308 PMC2796818
  54. Omasits U., Ahrens C. H., Müller S. & Wollscheid B. Protter: interactive protein feature visualization and integration with experimental proteomic data. Bioinformatics 30, 884– 886 (2014). 24162465
  55. Cox J. & Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367– 1372 (2008). 19029910
  56. Mehlem A., Hagberg C. E., Muhl L., Eriksson U. & Falkevall A. Imaging of neutral lipids by oil red O for analyzing the metabolic status in health and disease. Nat. Protoc. 8, 1149– 1154 (2013). 23702831
  57. Rakotondrafara A. M. & Hentze M. W. An efficient factor-depleted mammalian in vitro translation system. Nat. Protoc. 6, 563– 571 (2011). 21527914
  58. Rajeev K. G. et al. Hepatocyte-specific delivery of siRNAs conjugated to novel non-nucleosidic trivalent N-acetylgalactosamine elicits robust gene silencing in vivo. Chembiochem 16, 903– 908 (2015). 25786782
  59. Nair J. K. et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J. Am. Chem. Soc. 136, 16958– 16961 (2014). 25434769

Authors
Mobin, M. B., Gerstberger, S., Teupser, D., Campana, B., Charisse, K., Heim, M. H., Manoharan, M., Tuschl, T., & Stoffel, M.
Affiliations
  • ETH Zurich (CH)
  • Howard Hughes Medical Institute (US)
  • Institut für Laboratoriumsmedizin (DE)
  • University Hospital of Basel (CH)
  • Alnylam Pharmaceuticals (United States) (US)
Corresponding author
Stoffel, Markus
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2016-09-26
Volume
7
Issue
1
Pages
12848-12848
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms12848
PMC
PMC5052685
OpenAlex
W2526400916
Cited by
55
References
66
Citations by year
2026: 4 · 2025: 8 · 2024: 9 · 2023: 4 · 2022: 4 · 2021: 5 · 2020: 7 · 2019: 5 · 2018: 5 · 2017: 4
FWCI
2.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • edoc (University of Basel) (submittedVersion)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
  • ETH Zürich Research Collection (cc-by)
Funders
  • National Science Foundation
  • Howard Hughes Medical Institute
  • Boehringer Ingelheim Fonds
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030B _147089/1, 310030B, 147089, 310030)
  • National Institutes of Health
  • National Institute of General Medical Sciences (R01GM104962)
  • FP7 Ideas: European Research Council (250210)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
vigilin, RNA-binding proteins, VLDL secretion, apolipoprotein B, mRNA translation, post-transcriptional regulation, apolipoprotein C-III, fibronectin, hepatic lipid metabolism, hepatic steatosis, obesity, atherosclerosis, Ldlr-deficient mice, cardiovascular disease treatment

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