title: Macrophage sortilin promotes LDL uptake, foam cell formation, and atherosclerosis.
abstract: BACKGROUND
  Noncoding gene variants at the SORT1 locus are strongly associated with low-density lipoprotein cholesterol (LDL-C) levels, as well as with coronary artery disease. SORT1 encodes a protein called sortilin, and hepatic sortilin modulates LDL metabolism by targeting apolipoprotein B-containing lipoproteins to the lysosome. Sortilin is also expressed in macrophages, but its role in macrophage uptake of LDL and in atherosclerosis independent of plasma LDL-C levels is unknown.
  
  
  OBJECTIVE
  To determine the effect of macrophage sortilin expression on LDL uptake, foam cell formation, and atherosclerosis.
  
  
  RESULTS
  We crossed Sort1(-/-) mice onto a humanized Apobec1(-/-); hAPOB transgenic background and determined that Sort1 deficiency on this background had no effect on plasma LDL-C levels but dramatically reduced atherosclerosis in the aorta and aortic root. To test whether this effect was a result of macrophage sortilin deficiency, we transplanted Sort1(-/-);LDLR(-/-) or Sort1(+/+);LDLR(-/-) bone marrow into Ldlr(-/-) mice and observed a similar reduction in atherosclerosis in mice lacking hematopoetic sortilin without an effect on plasma LDL-C levels. In an effort to determine the mechanism by which hematopoetic sortilin deficiency reduced atherosclerosis, we found no effect of sortilin deficiency on macrophage recruitment or lipopolysaccharide-induced cytokine release in vivo. In contrast, sortilin-deficient macrophages had significantly reduced uptake of native LDL ex vivo and reduced foam cell formation in vivo, whereas sortilin overexpression in macrophages resulted in increased LDL uptake and foam cell formation.
  
  
  CONCLUSIONS
  Macrophage sortilin deficiency protects against atherosclerosis by reducing macrophage uptake of LDL. Sortilin-mediated uptake of native LDL into macrophages may be an important mechanism of foam cell formation and contributor to atherosclerosis development.
authors.affiliation: From the Department of Medicine (K.M.P., A.S., J.T., J.B., J.M., D.J.R.) and Department of Genetics (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (X.J., H.K.); and Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada (C.R.M.).
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Patel
authors.affiliation: From the Department of Medicine (K.M.P., A.S., J.T., J.B., J.M., D.J.R.) and Department of Genetics (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (X.J., H.K.); and Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada (C.R.M.).
authors.forename: Alanna
authors.initials: A
authors.lastname: Strong
authors.affiliation: From the Department of Medicine (K.M.P., A.S., J.T., J.B., J.M., D.J.R.) and Department of Genetics (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (X.J., H.K.); and Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada (C.R.M.).
authors.forename: Junichiro
authors.initials: J
authors.lastname: Tohyama
authors.affiliation: From the Department of Medicine (K.M.P., A.S., J.T., J.B., J.M., D.J.R.) and Department of Genetics (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (X.J., H.K.); and Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada (C.R.M.).
authors.forename: Xueting
authors.initials: X
authors.lastname: Jin
authors.affiliation: From the Department of Medicine (K.M.P., A.S., J.T., J.B., J.M., D.J.R.) and Department of Genetics (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (X.J., H.K.); and Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada (C.R.M.).
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Morales
authors.affiliation: From the Department of Medicine (K.M.P., A.S., J.T., J.B., J.M., D.J.R.) and Department of Genetics (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (X.J., H.K.); and Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada (C.R.M.).
authors.forename: Jeffery
authors.initials: J
authors.lastname: Billheimer
authors.affiliation: From the Department of Medicine (K.M.P., A.S., J.T., J.B., J.M., D.J.R.) and Department of Genetics (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (X.J., H.K.); and Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada (C.R.M.).
authors.forename: John
authors.initials: J
authors.lastname: Millar
authors.affiliation: From the Department of Medicine (K.M.P., A.S., J.T., J.B., J.M., D.J.R.) and Department of Genetics (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (X.J., H.K.); and Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada (C.R.M.).
authors.forename: Howard
authors.initials: H
authors.lastname: Kruth
authors.affiliation: From the Department of Medicine (K.M.P., A.S., J.T., J.B., J.M., D.J.R.) and Department of Genetics (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (X.J., H.K.); and Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada (C.R.M.). rader@mail.med.upenn.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000071479:APOBEC-1 Deaminase; D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001018:Aortic Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D001854:Bone Marrow Cells / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood; D003564:Cytidine Deaminase / Q000235:genetics; D066273:Diet, Western / Q000009:adverse effects; D005260:Female; D005487:Foam Cells / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011828:Radiation Chimera; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000099183:Sortilin
chemical_list: D000071479:APOBEC-1 Deaminase; D033942:Adaptor Proteins, Vesicular Transport; D008078:Cholesterol, LDL; D003564:Cytidine Deaminase; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D000099183:Sortilin; C000605090:Apobec1 protein, mouse
keywords: atherosclerosis; foam cell; low-density lipoprotein cholesterol; macrophage; receptor-mediated endocytosis