Evidence map›Paper›PMID 25593281›Full record

ArticleCirculation research2015

Macrophage sortilin promotes LDL uptake, foam cell formation, and atherosclerosis.

Kevin M Patel, Alanna Strong, Junichiro Tohyama, Xueting Jin, Carlos R Morales, Jeffery Billheimer, John Millar, Howard Kruth, Daniel J Rader

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers.

0numbers the graph read from it
0cells of the map it votes in
85citing papers in PubMed
15.1field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

85 citing papers in PubMed, 187 citations in OpenAlex.

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  12. Review
  13. The influence of metabolic disorders on adaptive immunity.Cellular & molecular immunology · 2024
    Review
  14. Sortilin and its potential role in cardiovascular pathology.The Egyptian heart journal : (EHJ) : official bulletin of the Egyptian Society of Cardiology · 2024
    Review
  15. What Causes Premature Coronary Artery Disease?Current atherosclerosis reports · 2024
    Review
  16. Article
  17. Review
  18. Review
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  20. Article

25 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

9 authors at 2 institutions in 1 country.

Kevin M PatelFrom 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.).
Alanna StrongFrom 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.).
Junichiro TohyamaFrom 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.).
Xueting JinFrom 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.).
Carlos R MoralesFrom 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.).
Jeffery BillheimerFrom 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.).
John MillarFrom 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.).
Howard KruthFrom 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.).
Daniel J RaderFrom 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.
National Institutes of Health · USNational Heart Lung and Blood Institute · US

Funding

Mechanism Of Cholesterol Accumulation In Human AtherosclerosisZIAHL002832 · NHLBI · NATIONAL HEART, LUNG, AND BLOOD INSTITUTE · PI KRUTH, HOWARD S · 2009 to 2019
$12.3M
PREDOCTORAL TRAINING PROGRAM IN PHARMACOLOGYT32GM008076 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI BLENDY, JULIE A · 1985 to 2023
$10.8M
Interrogation of novel pathways regulating VLDL production and plasma lipidsR01HL109489 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI RADER, DANIEL JAMES · 2011 to 2014
$1.6M
NHLBI NIH HHS R01 HL109489NHLBI NIH HHS R01HL109489NIGMS NIH HHS T32 GM008076NIGMS NIH HHS T32GM008076-30
6 · The paper itself

Abstract

rationaleNoncoding 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.

objectiveTo determine the effect of macrophage sortilin expression on LDL uptake, foam cell formation, and atherosclerosis. METHODS AND

resultsWe 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.

conclusionsMacrophage 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.

Indexed as

Adaptor Proteins, Vesicular TransportAnimalsAortic DiseasesAPOBEC-1 DeaminaseAtherosclerosisBone Marrow CellsCholesterol, LDLCytidine DeaminaseDiet, WesternFemaleFoam CellsLipoproteins, LDLMacrophagesMacrophages, PeritonealMaleMiceAdaptor Proteins, Vesicular TransportAPOBEC-1 DeaminaseApobec1 protein, mouseCholesterol, LDLCytidine DeaminaseLipoproteins, LDLReceptors, LDLSortilinatherosclerosisfoam celllow-density lipoprotein cholesterolmacrophagereceptor-mediated endocytosis

Identifiers

PMID25593281
PMCPMC4602371
OpenAlexW2039791966

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.