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Current Atherosclerosis Reports

, Volume 14, Issue 3, pp 211–218 | Cite as

Sortilin as a Regulator of Lipoprotein Metabolism

  • Alanna Strong
  • Daniel J. RaderEmail author
Genetics (AJ Marian, Section Editor)

Abstract

Elevated low-density lipoprotein cholesterol (LDL-C) is associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) and myocardial infarction (MI). Much of the insight into LDL metabolism has been gained through the study of Mendelian disorders of lipid metabolism. Genome-wide associations studies (GWAS) are now being used to identify novel genes and loci that contribute to variations in LDL-C levels, and they have identified the SORT1 gene as an important modulator of LDL-C levels and ASCVD risk. Mechanistic studies in mice and cell culture also suggest that the SORT1 gene is an important regulator of lipoprotein metabolism; however, these studies disagree on the directionality of the effect of Sort1 expression on plasma lipids and the mechanism for the lipid changes. Here we review the identification of the SORT1 locus as a modulator of LDL-C levels and ASCVD risk and the first mechanistic studies that explore the role of Sortilin in lipid metabolism.

Keywords

Sort1 Genome wide association study Atherosclerotic cardiovascular disease Low-density lipoprotein cholesterol Lipid metabolism 

Notes

Disclosure

No conflicts of interest relevant to this article were reported.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Lloyd-Jones D, et al. Executive summary: heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation. 2010;121:948–54.Google Scholar
  2. 2.
    Lusis AJ. Atherosclerosis. Nature. 2000;407:233–41.PubMedCrossRefGoogle Scholar
  3. 3.
    Waters DD, et al. Lipid treatment assessment project 2: a multinational survey to evaluate the proportion of patients achieving low-density lipoprotein cholesterol goals. Circulation. 2009;120:28–34.PubMedCrossRefGoogle Scholar
  4. 4.
    Hobbs HaD. In: Harrison’s principles of internal medicine. McGraw Hill; 2007. pp. 2416–29.Google Scholar
  5. 5.
    Kathiresan S, et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 2008;40:189–97.PubMedCrossRefGoogle Scholar
  6. 6.
    Willer CJ, et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 2008;40:161–9.PubMedCrossRefGoogle Scholar
  7. 7.
    • Kathiresan S, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2009;41:56–65. This is a genome-wide association study in European populations identifying 10 novel genetic determinants of lipid traits.PubMedCrossRefGoogle Scholar
  8. 8.
    • Teslovich TM, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466;707–13. This is the largest genome-wide association study for lipid traits, and it identified 95 total loci associated with lipid traits, including 59 novel loci. Many of these loci were replicated in non-European populations as well. This study named the SORT1 locus as a genome-wide significant determinant of LDL-C levels and cardiovascular disease risk in European and non-European populations with the lowest P-value in the human genome for LDL-C. Google Scholar
  9. 9.
    Samani NJ, et al. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007;357:443–53.PubMedCrossRefGoogle Scholar
  10. 10.
    • Schunkert H, et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet. 2011;43:333–8. This large-scale genome-wide association study for cardiovascular disease with 135,000 individuals of European descent identified 13 novel loci for CAD. Google Scholar
  11. 11.
    Qi L, et al. Genetic risk score and risk of myocardial infarction in Hispanics. Circulation. 2011;123;374–80.Google Scholar
  12. 12.
    Zhou L, et al. Genetic variants at newly identified lipid loci are associated with coronary heart disease in a Chinese Han population. PLoS One. 2011;6:e27481.Google Scholar
  13. 13.
    • Kathiresan S, et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet. 2009;41:334–41. This is a genome-wide association study of cardiovascular disease and early-onset myocardial infarction.PubMedCrossRefGoogle Scholar
  14. 14.
    Chasman DI, et al. Genetic loci associated with plasma concentration of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A1, and Apolipoprotein B among 6382 white women in genome-wide analysis with replication. Circ Cardiovasc Genet. 2008;1:21–30.PubMedCrossRefGoogle Scholar
  15. 15.
    • Linsel-Nitschke P, et al. Genetic variation at chromosome 1p13.3 affects sortilin mRNA expression, cellular LDL-uptake and serum LDL levels which translates to the risk of coronary artery disease. Atherosclerosis. 2010;208:183–9. This is the first mechanistic study associating elevated Sort1 expression with increased LDL uptake. Google Scholar
  16. 16.
    Nakayama K, et al. Large scale replication analysis of loci associated with lipid concentrations in a Japanese population. J Med Genet. 2009;46:370–4.PubMedCrossRefGoogle Scholar
  17. 17.
    • Musunuru K, et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature. 2010;466:714–9. This study identified the causal SNP at the 1p13 locus that confers the expression changes seen with the minor allele and in vivo proof of principles studies showing that Sort1 overexpression reduces plasma cholesterol and VLDL secretion, whereas Sort1 knockdown increases plasma cholesterol and VLDL secretion. Google Scholar
  18. 18.
    Gupta R, et al. Association of common DNA sequence variants at 33 genetic loci with blood lipids in individuals of African ancestry from Jamaica. Hum Genet. 2010;128:557–61.Google Scholar
  19. 19.
    Keebler ME, et al. Association of blood lipids with common DNA sequence variants at 19 genetic loci in the multiethnic United States National Health and Nutrition Examination Survey III. Circ Cardiovasc Genet. 2009;2:238–43.PubMedCrossRefGoogle Scholar
  20. 20.
    Nielsen MS, et al. The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein. EMBO J. 2001;20:2180–90.PubMedCrossRefGoogle Scholar
  21. 21.
    Nykjaer A, et al. Sortilin is essential for proNGF-induced neuronal cell death. Nature. 2004;427:843–8.PubMedCrossRefGoogle Scholar
  22. 22.
    • Hu F, et al. Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron. 2010;68:654–67. This study shows that SORT1 mediates the lysosomal degradation of progranulin and shows a functional relationship between sortilin and frontotemporal dementia. Google Scholar
  23. 23.
    Navarro V, Vincent JP, Mazella J. Shedding of the luminal domain of the neurotensin receptor-3/sortilin in the HT29 cell line. Biochem Biophys Res Commun. 2002;298:760–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Evans SF, et al. Neuronal brain-derived neurotrophic factor is synthesized in excess, with levels regulated by sortilin-mediated trafficking and lysosomal degradation. J Biol Chem. 2011;286:29556–67.Google Scholar
  25. 25.
    Nielsen MS, Jacobsen C, Olivecrona G, Gliemann J, Petersen CM. Sortilin/neurotensin receptor-3 binds and mediates degradation of lipoprotein lipase. J Biol Chem. 1999;274:8832–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Jacobsen L, et al. Activation and functional characterization of the mosaic receptor SorLA/LR11. J Biol Chem. 2001;276:22788–96.PubMedCrossRefGoogle Scholar
  27. 27.
    Nilsson SK, et al. Endocytosis of apolipoprotein A-V by members of the low density lipoprotein receptor and the VPS10p domain receptor families. J Biol Chem. 2008;283:25920–7.PubMedCrossRefGoogle Scholar
  28. 28.
    • Kjolby M, et al. Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export. Cell Metab. 2010;12:213–23. This is a mechanistic studies using a SORT−/− mouse that suggest that Sort1 deficiency is associated with reduced plasma cholesterol and reduced VLDL secretion. Google Scholar
  29. 29.
    • Ai D, Baez JM, Jiang H, Conlon D, Hernandez-Ono A, Frank-Kamenetsky M, Milstein S, et al. Activation of ER stress and mTORC1 supresses hepatic sortilin-1 levels in obese mice. J Clin Investi. 2012; Apr 2 [Epub ahead of print]. This is a study showing that Sort1 expression is regulated by ER stress and mTOR signaling and demonstrating that elevated Sort1 expression is associated with reductions in VLDL/apoB secretion whereas reduced Sort1 expression is associated with increased VLDL/apoB secretion. Google Scholar
  30. 30.
    Jansen P, et al. Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury. Nat Neurosci. 2007;10:1449–57.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  2. 2.Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA

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