The DOI matches its Crossref record; 23 of the 23 references it cites were found in a registry or an index; none of the 17 sources its claims cite is checked for support yet.
Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis
Open accessAbstract
Rationale: 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. Methods and 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.
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TL;DR
Macrophage sortilin promotes native LDL uptake, foam cell formation, and atherosclerosis in mouse models, independent of plasma LDL-C levels. Sort1 deficiency in hematopoietic cells reduces atherosclerosis, whereas sortilin overexpression increases macrophage LDL uptake.
Key findings
- Total-body Sort1 deficiency on the Apobec1−/−; hAPOB Tg background did not change plasma LDL-C but reduced atherosclerosis: 68% reduction in en face aorta lesion area (P<0.0001) and 87% reduction in aortic root lesion area (P<0.0001).
- Hematopoietic Sort1 deficiency after bone marrow transplantation into Ldlr−/− mice also reduced atherosclerosis without affecting plasma LDL-C: 69% reduction in en face aortic lesion area (P<0.00001) and 34% reduction in aortic root lesion area (P<0.01).
- Sortilin-deficient macrophages had reduced foam cell formation: 28% lower total cellular cholesterol, 25% lower free cholesterol, and 32% lower cholesteryl ester (P<0.05); in vivo foam cells showed a 33% reduction in cellular cholesterol (P<0.05).
- Sortilin deficiency reduced 125I-LDL uptake by 48% in thioglycollate-elicited macrophages and 33% in bone marrow-derived macrophages (P<0.05 for both), by 39% in the absence of LDLR (P<0.05), and by 38% with cytochalasin D (P<0.05); Sort1 overexpression in J774 macrophages increased LDL uptake by 29% (P<0.05). No effect was found on thioglycollate-elicited monocyte recruitment or LPS-induced cytokine release in vivo.
Methods
- Atherosclerosis studies used Sort1−/− mice crossed onto the Apobec1−/−; hAPOB Tg background, fed a western-type diet for 18 weeks, with lesion area assessed en face and in aortic roots.
- Bone marrow from Sort1−/−;LDLR−/− or Sort1+/+;LDLR−/− donors was transplanted into irradiated Ldlr−/− recipients; after 6 weeks, mice received western diet for 18 weeks before atherosclerosis assessment.
- Macrophage studies used thioglycollate-elicited peritoneal macrophages and bone marrow-derived macrophages, with 125I-LDL uptake/degradation, Oil Red O staining, cholesterol measurements, and lentiviral Sort1 overexpression in J774 cells; statistics used 2-tailed paired Student’s t test and 1-way ANOVA with Bonferroni correction for the LPS experiment.
Limitations
- The paper does not include a formal limitations section. It states that the mechanisms of LDL-induced macrophage Sort1 upregulation require further exploration.
- Evident from the text: all causal data are from mouse atherosclerosis models and ex vivo mouse macrophages; bone marrow transplantation implicates hematopoietic cells but does not isolate macrophages from other hematopoietic cell types.
- Evident from the text: no human interventional or macrophage-specific in vivo data are presented, and the authors note mechanistic differences from another study using a different mouse model and LDL-labeling approach.
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Claims the paper makes
21 Own result · 10 Own interpretation · 7 Not checked yet · 2 Own method · 1 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sort1 deficiency was associated with a 39% percent reduction in LDL uptake in the absence of the LDLR (P<0.05; Figure 4f).”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Macrophage sortilin deficiency reduces LDL uptake and foam cell formation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“There was no difference in macrophage counts between Sort1+/+ and Sort −/− mice (Online Figure IIa).”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Sortilin deficiency has no effect on thioglycollate-elicited monocyte recruitment or LPS-induced inflammatory response in vivo
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Sort1 deficient macrophages had a significant 28% reduction in total cellular cholesterol”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Macrophage sortilin deficiency reduces LDL uptake and foam cell formation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Sort1 overexpression in macrophages led to a 29% increase in LDL uptake (P< 0.05; Figure 4e).”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Macrophage sortilin deficiency reduces LDL uptake and foam cell formation
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In the paper
“a 25% reduction in free cholesterol”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Macrophage sortilin deficiency reduces LDL uptake and foam cell formation
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“and a significant 33% reduction in cellular cholesterol content compared to macrophages isolated from Sort1+/+ mice (P<0.05; Figure 3e–f).”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Macrophage sortilin deficiency reduces LDL uptake and foam cell formation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sort1−/−;Ldlr−/− macrophages had a clear and consistent reduction in Oil Red O staining (Figure 3a).”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Macrophage sortilin deficiency reduces LDL uptake and foam cell formation
boosted- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sort1 mRNA abundance increased over 400-fold with LDL incubation (P <0.05; Figure 4a)”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Macrophage sortilin deficiency reduces LDL uptake and foam cell formation
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sort1 deficiency was associated with a 48% and 33% percent reduction in LDL uptake, respectively (P <0.05 for both; Figure 4c–d).”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Macrophage sortilin deficiency reduces LDL uptake and foam cell formation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mice transplanted with Sort1−/−;Ldlr−/− bone marrow had a 69% reduction in en face aortic lesion area (P<0.00001)”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Sortilin deficiency in hematopoetic cells protects against atherosclerosis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“sortilin protein also increased significantly with LDL incubation (Figure 4b).”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Macrophage sortilin deficiency reduces LDL uptake and foam cell formation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sort1 deficiency was associated with a 48% and 33% percent reduction in LDL uptake, respectively (P <0.05 for both; Figure 4c–d).”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Macrophage sortilin deficiency reduces LDL uptake and foam cell formation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and a 32% reduction in cholesteryl ester (P<0.05; Figure 3b–d).”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Macrophage sortilin deficiency reduces LDL uptake and foam cell formation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“On this genetic background, total and LDL cholesterol levels were not different in Sort1−/− mice compared with Sort1+/+ mice (Figure 1a,b).”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Sortilin deficiency in hematopoetic cells protects against atherosclerosis
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After 18 weeks on diet, Sort1−/− mice had a 68% reduction in en face aorta lesion area (P <0.0001 Figure 1c,d)”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Sortilin deficiency in hematopoetic cells protects against atherosclerosis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and an 87% reduction in aortic root lesion area (P <0.0001 Figure 1e,f) compared with Sort1+/+ mice”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Sortilin deficiency in hematopoetic cells protects against atherosclerosis
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“without an effect on plasma LDL-C levels”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > Abstract > Methods and Results
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sort1 deficiency was associated with a 38% reduction in LDL uptake in the presence of cytochalasin D (P< 0.05; Figure 4f).”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Macrophage sortilin deficiency reduces LDL uptake and foam cell formation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“macrophages isolated from Sort1−/− mice had reduced Oil Red O staining”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Macrophage sortilin deficiency reduces LDL uptake and foam cell formation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Cytokine levels post LPS injection were found to be similar between Sort1−/− and Sort1 +/+ (Online Figure IIb,c).”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Sortilin deficiency has no effect on thioglycollate-elicited monocyte recruitment or LPS-induced inflammatory response in vivo
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and a 34% reduction in aortic root lesion area (P < 0.01) compared to mice transplanted with Sort1+/+;Ldlr−/− bone marrow”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Sortilin deficiency in hematopoetic cells protects against atherosclerosis
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Macrophage sortilin deficiency protects against atherosclerosis by reducing macrophage uptake of LDL.”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > Abstract > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Thioglycollate-elicited peritoneal macrophages and bone-marrow-derived macrophages are representative of arterial macrophages for LDL uptake and foam cell formation.
None of the sources cited for this claim have been checked yet.
In the paper
“Sortilin is also expressed in macrophages, but little is known about its function in this cell type or its relationship to atherosclerosis.14, 15”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > INTRODUCTION
What the sources say
- Not checked yetcites [14] Wahe A Kasmapour B Schmaderer C Liebl D Sandhoff K Nykjaer A Griffiths G Gutierrez MG Golgi-to-phagosome transport of acid sphingomyelinase and prosaposin is mediated by sortilin Journal of cell science 2010 123 2502 2511 20571055
- Not checked yetcites [15] Wong I Liao H Bai X Zaknic A Zhong J Guan Y Li HY Wang YJ Zhou XF Probdnf inhibits infiltration of ed1+ macrophages after spinal cord injury Brain, behavior, and immunity 2010 24 585 597 20083190
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we show here that macrophage sortilin promotes macrophage LDL uptake, foam cell formation, and atherosclerosis independent of plasma LDL-C levels.”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > INTRODUCTION
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we conclude that macrophage sortilin promotes LDL uptake, foam cell formation, and atherosclerosis”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We also found that increasing concentrations of extracellular LDL causes an upregulation of macrophage Sort1 mRNA and protein.”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we conclude that macrophage sortilin promotes LDL uptake, foam cell formation, and atherosclerosis”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Thioglycollate-elicited peritoneal macrophages and bone-marrow-derived macrophages are representative of arterial macrophages for LDL uptake and foam cell formation.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we conclude that macrophage sortilin promotes LDL uptake, foam cell formation, and atherosclerosis”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Thioglycollate-elicited peritoneal macrophages and bone-marrow-derived macrophages are representative of arterial macrophages for LDL uptake and foam cell formation.
- Probably not a substantial claim. 6
- It may state two separate claims as one. 9
None of the sources cited for this claim have been checked yet.
In the paper
“The SORT1 gene, encoding the protein sortilin, appears to be the causal gene at the locus regulating LDL cholesterol levels9–11.”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > INTRODUCTION
What the sources say
- Not checked yetcites [9] Kjolby M Andersen OM Breiderhoff T Fjorback AW Pedersen KM Madsen P Jansen P Heeren J Willnow TE Nykjaer A Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export Cell metabolism 2010 12 213 223 20816088
- Not checked yetcites [10] Strong A Ding Q Edmondson AC Millar JS Sachs KV Li X Kumaravel A Wang MY Ai D Guo L Alexander ET Nguyen D Lund-Katz S Phillips MC Morales CR Tall AR Kathiresan S Fisher EA Musunuru K Rader DJ Hepatic sortilin regulates both apolipoprotein b secretion and ldl catabolism The Journal of clinical investigation 2012 122 2807 2816 22751103 PMC3408750
- Not checked yetcites [11] Strong A Patel K Rader DJ Sortilin and lipoprotein metabolism: Making sense out of complexity Current opinion in lipidology 2014 25 350 357 25101658 PMC4565516
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The macrophage sortilin pathway is a novel pathway of macrophage cholesterol loading that quantitatively contributes to atherosclerosis.”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data establish macrophage sortilin as the first receptor-mediated pathway of uptake of native LDL leading to foam cell formation and promoting atherosclerosis development.”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > DISCUSSION
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“non-coding genetic variants at chromosome 1p13 were reported to be significantly associated with myocardial infarction and CAD3, a finding that has been widely replicated4, 5. The same variants have also shown to be significantly associated with plasma levels of LDL cholesterol6–8.”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > INTRODUCTION
What the sources say
- Not checked yetcites [3] Samani NJ Erdmann J Hall AS Genomewide association analysis of coronary artery disease The New England journal of medicine 2007 357 443 453 17634449 PMC2719290
- Not checked yetcites [4] Kathiresan S Voight BF Purcell S Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants Nature genetics 2009 41 334 341 19198609 PMC2681011
- Not checked yetcites [5] Willer CJ Sanna S Jackson AU Newly identified loci that influence lipid concentrations and risk of coronary artery disease Nature genetics 2008 40 161 169 18193043 PMC5206900
- Not checked yetcites [6] Kathiresan S Melander O Guiducci C Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans Nature genetics 2008 40 189 197 18193044 PMC2682493
- Not checked yetcites [7] Musunuru K Strong A Frank-Kamenetsky M From noncoding variant to phenotype via sort1 at the 1p13 cholesterol locus Nature 2010 466 714 719 20686566 PMC3062476
- Not checked yetcites [8] Teslovich TM Musunuru K Smith AV Biological, clinical and population relevance of 95 loci for blood lipids Nature 2010 466 707 713 20686565 PMC3039276
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
In the paper
“Kruth and colleagues have shown that macrophages internalize native LDL through a process of macropinocytosis, although LDL uptake cannot be fully accounted for by this process1.”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > INTRODUCTION
What the sources say
- Not checked yetcites [1] Barthwal MK Anzinger JJ Xu Q Bohnacker T Wymann MP Kruth HS Fluid-phase pinocytosis of native low density lipoprotein promotes murine m-csf differentiated macrophage foam cell formation PloS one 2013 8 e58054 23536783 PMC3594233
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Sortilin-mediated uptake of native LDL into macrophages may be an important mechanism of foam cell formation and contributor to atherosclerosis development.”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > Abstract > Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“hepatic sortilin binds LDL and promotes its cellular uptake and lysosomal degradation10.”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > INTRODUCTION
What the sources say
- Not checked yetcites [10] Strong A Ding Q Edmondson AC Millar JS Sachs KV Li X Kumaravel A Wang MY Ai D Guo L Alexander ET Nguyen D Lund-Katz S Phillips MC Morales CR Tall AR Kathiresan S Fisher EA Musunuru K Rader DJ Hepatic sortilin regulates both apolipoprotein b secretion and ldl catabolism The Journal of clinical investigation 2012 122 2807 2816 22751103 PMC3408750
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These studies indicate that macrophage sortilin deficiency reduces macrophage uptake of LDL and formation of foam cells and this effect is independent of the LDL receptor and of macropinocytosis.”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Macrophage sortilin deficiency reduces LDL uptake and foam cell formation
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Thioglycollate-elicited peritoneal macrophages and bone-marrow-derived macrophages are representative of arterial macrophages for LDL uptake and foam cell formation.
- Rests on an assumption: Cytochalasin D completely inhibits macropinocytosis under the experimental conditions, so residual LDL uptake is independent of macropinocytosis.
None of the sources cited for this claim have been checked yet.
In the paper
“The SORT1 gene, encoding the protein sortilin, appears to be the causal gene at the locus regulating LDL cholesterol levels9–11.”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > INTRODUCTION
What the sources say
- Not checked yetcites [9] Kjolby M Andersen OM Breiderhoff T Fjorback AW Pedersen KM Madsen P Jansen P Heeren J Willnow TE Nykjaer A Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export Cell metabolism 2010 12 213 223 20816088
- Not checked yetcites [10] Strong A Ding Q Edmondson AC Millar JS Sachs KV Li X Kumaravel A Wang MY Ai D Guo L Alexander ET Nguyen D Lund-Katz S Phillips MC Morales CR Tall AR Kathiresan S Fisher EA Musunuru K Rader DJ Hepatic sortilin regulates both apolipoprotein b secretion and ldl catabolism The Journal of clinical investigation 2012 122 2807 2816 22751103 PMC3408750
- Not checked yetcites [11] Strong A Patel K Rader DJ Sortilin and lipoprotein metabolism: Making sense out of complexity Current opinion in lipidology 2014 25 350 357 25101658 PMC4565516
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Body, liver and spleen weights, plasma cholesterol, peripheral blood counts, and hepatic Sort1 expression were similar between groups (Online Figure I).”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Sortilin deficiency in hematopoetic cells protects against atherosclerosis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Bone marrow engraftment was 74% (Online Figure Ia).”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > RESULTS > Sortilin deficiency in hematopoetic cells protects against atherosclerosis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“Gene deletion of known receptors of modified LDL, such as scavenger receptor A (SRA) and CD36, do not reduce foam cell formation or the development of atherosclerosis in mice2.”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > INTRODUCTION
What the sources say
- Not checked yetcites [2] Steinberg D The ldl modification hypothesis of atherogenesis: An update Journal of lipid research 2009 50 Suppl S376 381 19011257 PMC2674707
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“hepatic sortilin modulates LDL metabolism by targeting apoB-containing lipoproteins to the lysosome.”
§ Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis > Abstract > Rationale
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
The paper relies on this without support.
Thioglycollate-elicited peritoneal macrophages and bone-marrow-derived macrophages are representative of arterial macrophages for LDL uptake and foam cell formation.
“For studies of macrophage LDL uptake, both thioglycollate-elicited peritoneal macrophages and bone-marrow derived macrophages were used.”
The paper relies on this without support.
Cytochalasin D completely inhibits macropinocytosis under the experimental conditions, so residual LDL uptake is independent of macropinocytosis.
“LDL uptake studies were performed in bone marrow derived macrophages in the presence of cytochalasin D, a potent inhibitor of actin polymerization and macropinocytosis.”
The paper relies on this without support.
LPS-induced cytokine release in vivo is a valid measure of the inflammatory pathways that contribute to atherosclerosis in this model.
“To determine if Sort1−/− mice have reduced cytokine levels, cytokine multiplexing assays were performed on Sort1−/− and Sort1+/+ mice injected with lipopolysaccharide (LPS).”
Citations
Cites
Biological, clinical and population relevance of 95 loci for blood lipids
Teslovich, T. M., Musunuru, K., Smith, A. V., Edmondson, A. C., Stylianou, I. M., Koseki, M., Pirruccello, J. P., Ripatti, S., Chasman, D. I., Willer, C. J., et al. (2010) · Nature · doi:10.1038/nature09270 · Cited by 3,487
Genomewide Association Analysis of Coronary Artery Disease
Samani, N. J., Erdmann, J., Hall, A. S., Hengstenberg, C., Mangino, M., Mayer, B., Dixon, R. J., Meitinger, T., Braund, P., Wichmann, H.-E., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa072366 · Cited by 2,044
Newly identified loci that influence lipid concentrations and risk of coronary artery disease
Willer, C. J., Sanna, S., Jackson, A. U., Scuteri, A., Bonnycastle, L. L., Clarke, R., Heath, S. C., Timpson, N. J., Najjar, S. S., Stringham, H. M., et al. (2008) · Nature Genetics · doi:10.1038/ng.76 · Cited by 1,585
Kathiresan, S., Melander, O., Guiducci, C., Surti, A., Burtt, N. P., Rieder, M. J., Cooper, G. M., Roos, C., Voight, B. F., Havulinna, A. S., et al. (2008) · Nature Genetics · doi:10.1038/ng.75 · Cited by 1,386
From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus
Musunuru, K., Strong, A., Frank-Kamenetsky, M., Lee, N. E., Ahfeldt, T., Sachs, K. V., Li, X., Li, H., Kuperwasser, N., Ruda, V. M., et al. (2010) · Nature · doi:10.1038/nature09266 · Cited by 1,140
Self-citationMyocardial Infarction Genetics Consortium (2009) · Nature Genetics · doi:10.1038/ng.327 · Cited by 1,088
Self-citationThe LDL modification hypothesis of atherogenesis: an update
Steinberg, D. H. (2008) · Journal of Lipid Research · doi:10.1194/jlr.r800087-jlr200 · Cited by 474
Moore, K. J., Kunjathoor, V. V., Koehn, S. L., Manning, J. J., Tseng, A. A., Silver, J. M., McKee, M. L., & Freeman, M. W. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24061 · Cited by 386
Regression of Atherosclerosis Induced by Liver-Directed Gene Transfer of Apolipoprotein A-I in Mice
Tangirala, R. K., Tsukamoto, K., Chun, S. H., Usher, D. C., Puré, E., & Rader, D. J. (1999) · Circulation · doi:10.1161/01.cir.100.17.1816 · Cited by 355
Self-citationManning, J. J., Moore, K. J., Seimon, T. A., Bell, S. A., Sharuk, M., Alvarez-Leite, J. I., de Winther, M. P. J., Tabas, I. A., & Freeman, M. W. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.176644 · Cited by 282
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The Global Phosphorylation Landscape of SARS-CoV-2 Infection
Bouhaddou, M., Memon, D., Meyer, B., White, K. M., Rezelj, V. V., Marrero, M. C., Polacco, B. J., Melnyk, J. E., Ulferts, S., Kaake, R. M., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.034 · Cited by 1,018
Opportunities and challenges for transcriptome-wide association studies
Wainberg, M., Sinnott-Armstrong, N., Mancuso, N., Barbeira, A., Knowles, D. A., Golan, D., Ermel, R., Ruusalepp, A., Quertermous, T., Hao, K., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0385-z · Cited by 906
Sortilin mediates vascular calcification via its recruitment into extracellular vesicles
Goettsch, C., Hutcheson, J. D., Aikawa, M., Iwata, H., Pham, T., Nykjær, A., Kjølby, M., Rogers, M. A., Michel, T. M., Shibasaki, M., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci80851 · Cited by 263
Self-citationGenetics of Common, Complex Coronary Artery Disease
Musunuru, K., & Kathiresan, S. (2019) · Cell · doi:10.1016/j.cell.2019.02.015 · Cited by 246
Matrix Metalloproteinase in Abdominal Aortic Aneurysm and Aortic Dissection
Maguire, E. M., Pearce, S. W. A., Xiao, R., Oo, A., & Xiao, Q. (2019) · Pharmaceuticals · doi:10.3390/ph12030118 · Cited by 191
Metadata
- Authors
- Patel, K. M., Strong, A., Tohyama, J., Jin, X., Morales, C. R., Billheimer, J., Millar, J., Kruth, H., & Rader, D. J.
- Affiliations
- National Institutes of Health (US)
- Venue
- Circulation Research
- Published
- 2015-02-27
- Volume
- 116
- Issue
- 5
- Pages
- 789-796
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC4602371
- OpenAlex
- W2039791966
- Cited by
- 194
- References
- 23
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 19 · 2023: 10 · 2022: 24 · 2021: 15 · 2020: 21 · 2019: 20 · 2018: 22 · 2017: 17 · 2016: 15 · 2015: 10
- FWCI
- 9.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL109489)
- National Institute of General Medical Sciences (T32GM008076)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Keywords
- sortilin, SORT1, macrophages, LDL uptake, foam cell formation, atherosclerosis, LDL receptor, apolipoprotein B, coronary artery disease, bone marrow transplantation, humanized mice, lipid metabolism
- MeSH terms
- APOBEC-1 Deaminase, Sortilin, Animals, Aortic Diseases, Bone Marrow Cells, Cytidine Deaminase, Female, Foam Cells, Lipoproteins, LDL, Cholesterol, LDL, Macrophages, Male, Mice, Transgenic, Radiation Chimera, Receptors, LDL, Macrophages, Peritoneal, Mice, Knockout, Adaptor Proteins, Vesicular Transport, Atherosclerosis, Mice, Diet, Western
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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