title: Sortilin and lipoprotein metabolism: making sense out of complexity.
abstract: OBJECTIVE
  Genome-wide association studies have been used as an unbiased tool to identify novel genes that contribute to variations in LDL cholesterol levels in the hopes of uncovering new biology and new therapeutic targets for the treatment of atherosclerotic cardiovascular disease. The locus identified by genome-wide association studies with the strongest association with LDL cholesterol and atherosclerotic cardiovascular disease is the 1p13 sortilin-1 (SORT1) locus. Here, we review the identification and characterization of this locus, the initial physiological studies describing the role of SORT1 in lipoprotein metabolism, and recent work that has begun to sort out the complexity of this role.
  
  
  RESULTS
  Studies by several groups support an important role for sortilin in lipoprotein metabolism; however, the directionality of the effect of sortilin on plasma cholesterol and its role in the secretion of hepatic lipoproteins remains controversial. Studies by several groups support a role for sortilin in inhibiting lipoprotein export, whereas other studies suggest that sortilin facilitates lipoprotein export.
  
  
  CONCLUSIONS
  Understanding the mechanism by which sortilin affects LDL cholesterol will increase our understanding of the regulation of lipoprotein metabolism and hepatic lipoprotein export and may also allow us to harness the power of the 1p13 SORT1 locus for the treatment of atherosclerotic cardiovascular disease.
authors.affiliation: Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Alanna
authors.initials: A
authors.lastname: Strong
authors.forename: Kevin
authors.initials: K
authors.lastname: Patel
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D008078:Cholesterol, LDL / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D008078:Cholesterol, LDL; D000099183:Sortilin
references.citation: Atherosclerosis. 2010 Jan;208(1):183-9
references.pmid: 19660754
references.citation: Nature. 2004 Feb 26;427(6977):843-8
references.pmid: 14985763
references.citation: Circulation. 2010 Feb 23;121(7):948-54
references.pmid: 20177011
references.citation: J Biol Chem. 2011 Aug 26;286(34):29556-67
references.pmid: 21730062
references.citation: PLoS One. 2011;6(11):e28146
references.pmid: 22140527
references.citation: Bioessays. 2011 Jun;33(6):430-7
references.pmid: 21462369
references.citation: J Biol Chem. 1998 Feb 6;273(6):3582-7
references.pmid: 9452485
references.citation: Genetics. 2012 Nov;192(3):889-903
references.pmid: 22923381
references.citation: Nature. 2010 Aug 5;466(7307):714-9
references.pmid: 20686566
references.citation: Annu Rev Med. 2012;63:317-28
references.pmid: 22248326
references.citation: Atherosclerosis. 2012 Dec;225(2):370-5
references.pmid: 23102784
references.citation: PLoS One. 2012;7(6):e39975
references.pmid: 22768187
references.citation: J Lipid Res. 2013 Oct;54(10):2754-62
references.pmid: 23904453
references.citation: Rev Port Cardiol. 2013 Oct;32(10):793-9
references.pmid: 23910371
references.citation: J Biol Chem. 1999 Mar 26;274(13):8832-6
references.pmid: 10085125
references.citation: EMBO J. 2001 May 1;20(9):2180-90
references.pmid: 11331584
references.citation: Nat Genet. 2009 Jan;41(1):56-65
references.pmid: 19060906
references.citation: EMBO J. 2003 Dec 15;22(24):6430-7
references.pmid: 14657016
references.citation: N Engl J Med. 2007 Aug 2;357(5):443-53
references.pmid: 17634449
references.citation: J Am Soc Nephrol. 2010 Jan;21(1):82-92
references.pmid: 19875813
references.citation: FASEB J. 2014 Feb;28(2):978-97
references.pmid: 24165480
references.citation: Cell Death Differ. 2003 May;10(5):580-91
references.pmid: 12728256
references.citation: J Clin Invest. 2012 Aug;122(8):2807-16
references.pmid: 22751103
references.citation: PLoS One. 2014 Jan 03;9(1):e84969
references.pmid: 24404198
references.citation: J Clin Invest. 2013 Mar;123(3):1323-34
references.pmid: 23426179
references.citation: Nature. 2010 Aug 5;466(7307):707-13
references.pmid: 20686565
references.citation: Nature. 2000 Sep 14;407(6801):233-41
references.pmid: 11001066
references.citation: Nat Genet. 2011 Mar 06;43(4):333-8
references.pmid: 21378990
references.citation: J Lipid Res. 2013 Mar;54(3):649-661
references.pmid: 23307945
references.citation: EMBO J. 2009 Jun 3;28(11):1612-23
references.pmid: 19407813
references.citation: Curr Opin Lipidol. 2011 Apr;22(2):79-85
references.pmid: 21124217
references.citation: Cell Stem Cell. 2013 Feb 7;12(2):238-51
references.pmid: 23246482
references.citation: J Neurosci. 2013 Jan 2;33(1):358-70
references.pmid: 23283348
references.citation: Circ Res. 2011 Jan 21;108(2):158-60
references.pmid: 21252148
references.citation: Hum Mol Genet. 2013 Jul 15;22(14):2941-7
references.pmid: 23535823
references.citation: Cell Metab. 2014 Feb 4;19(2):310-8
references.pmid: 24506872
references.citation: Cell Metab. 2010 Sep 8;12(3):213-23
references.pmid: 20816088
references.citation: Brain Res. 2007 Dec 5;1183:32-42
references.pmid: 17964555
references.citation: Nat Genet. 2008 Feb;40(2):189-97
references.pmid: 18193044
references.citation: Neuron. 2010 Nov 18;68(4):654-67
references.pmid: 21092856
references.citation: Biochem Biophys Res Commun. 2013 Jan 4;430(1):66-71
references.pmid: 23159624
references.citation: J Biol Chem. 2011 Jun 17;286(24):21876-85
references.pmid: 21521695
references.citation: J Biol Chem. 1997 Feb 7;272(6):3599-605
references.pmid: 9013611
references.citation: Atherosclerosis. 2012 Dec;225(2):341-7
references.pmid: 23099119
references.citation: Biochem Biophys Res Commun. 2008 Aug 22;373(2):292-7
references.pmid: 18559255
references.citation: Nat Genet. 2008 Feb;40(2):161-9
references.pmid: 18193043
references.citation: J Clin Invest. 2012 May;122(5):1677-87
references.pmid: 22466652