Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice
Open accessAbstract
Lipoprotein glomerulopathy (LPG) is a renal disease often accompanied by dyslipidemia and increased serum apoE levels. apoESendai (Arg145Pro), a rare mutant based on the apoE3 sequence carrying an apoE2 charge, causes LPG in humans and transgenic mice, but its effects on the artery wall are unknown. Macrophage expression of apoESendai may also directly influence renal and arterial homeostasis. We investigated the effects of macrophage-expressed apoESendai in apoE(-/-) mice with or without LDL receptor (LDLR). Murine bone marrow transduced to express apoE2, apoE3, or apoESendai was transplanted into lethally irradiated mice. Macrophage apoESendai expression reduced aortic lesion size and inflammation by 32 and 28%, respectively, compared with apoE2 in apoE(-/-) recipients. No differences in lesion size or inflammation were found between apoESendai and apoE3 in apoE(-/-) recipients. Macrophage apoESendai expression also reduced aortic lesion size by 18% and inflammation by 29% compared with apoE2 in apoE(-/-)/LDLR(-/-) recipients. Glomerular lesions compatible with LPG with increased mesangial matrix, extracellular lipid accumulation, and focal mesangiolysis were only observed in apoE(-/-)/LDLR(-/-) mice expressing apoESendai. Thus, macrophage expression of apoESendai protects against atherosclerosis while causing lipoprotein glomerulopathy. This is the first demonstration of an apoprotein variant having opposing effects on vascular and renal homeostasis.
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Written from the paper’s full text.
TL;DR
Macrophage-derived apoE Sendai suppresses atherosclerosis in hyperlipidemic mice while causing lipoprotein glomerulopathy under severe hyperlipidemia. The effects are independent of serum cholesterol changes in apoE−/−/LDLR−/− mice.
Key findings
- In apoE−/− recipients, macrophage apoE Sendai reduced aortic lesion size and inflammation by 32% and 28%, respectively, compared with apoE2; no differences were found between apoE Sendai and apoE3.
- In apoE−/−/LDLR−/− DKO recipients, apoE Sendai reduced aortic lesion size by 18% and inflammation by 29% compared with apoE2, despite no differences in serum cholesterol.
- Glomerular lesions compatible with LPG—increased mesangial matrix, extracellular lipid accumulation, and focal mesangiolysis—were observed only in DKO mice expressing apoE Sendai. In apoE−/− recipients, apoE Sendai had a lower average glomerular injury score (0.5) than GFP (1 to 2+) or apoE2 (2+), but no actual LPG-like lesions.
- Serum cholesterol in apoE−/− recipients was 432 ± 63 mg/dl (GFP), 333 ± 62 mg/dl (apoE2), 183 ± 62 mg/dl (apoE3), and 259 ± 41 mg/dl (apoE Sendai). apoE Sendai weakly associated with LRP1 and was not retained in macrophages; an artificial apoE2-R145P mutant showed similar impaired LRP1 interaction and lack of retention.
Methods
- Bone marrow from 8-week-old apoE−/− mice was transduced with GFP, apoE2, apoE3, or apoE Sendai lentiviral constructs and transplanted into lethally irradiated 12-week-old male apoE−/− or 8-week-old apoE−/−/LDLR−/− DKO mice (5 × 10^6 cells); mice were kept on chow diet and assessed 8 weeks after bone marrow transplantation.
- Analyses included serum cholesterol and FPLC lipoprotein profiles, proximal aorta Oil Red O lesion area, Ly6C/CCR2 immunostaining, M1/M2 ratio, renal PAS/Jones semiquantitative injury scoring (0–3+), F4/80 macrophage staining, immunoprecipitation/Western blotting, and macrophage cholesterol efflux.
- Statistics used Mann-Whitney for atherosclerosis, Student’s t-test for other two-group comparisons, and ANOVA with Tukey’s post hoc test for more than two groups; n values included apoE−/− GFP 7, apoE2 10, apoE3 5, apoE Sendai 11, and DKO apoE2 4, apoE Sendai 3.
Limitations
- The authors state that lesion development was studied at an early stage (20 weeks), when plaque macrophages are mainly M2; M1 macrophage differentiation becomes dominant at more advanced stages (>55 weeks), which may explain the lack of M1/M2 differences.
- Evident from the text: DKO recipient groups were very small (apoE2 n = 4; apoE Sendai n = 3), only male mice were used, mice were on chow diet, and the endpoint was 8 weeks after BMT.
- Evident from the text: findings are from mouse bone marrow transplantation models and do not establish human clinical outcomes.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
24 of 72 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured
- Interpretationcitation
The impaired interaction of apoE Sendai with LRP1 may have functional consequences involving lesion inflammation.
“As LRP1 is also involved in macrophage infl ammation and signaling ( 16, 52, 53 ), the impaired interaction of apoE Sendai with LRP1 may also have functional consequences involving lesion infl ammation.”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [16] Yancey, 2011, Low-density lipoprotein receptor-related protein 1 prevents early atherosclerosis by limiting lesional apoptosis and inflammatory Ly-6Chigh monocytosis: evidence that the effects are not apolipoprotein E dependent, Circulation. source
- cites [52] May, 2013, The low-density lipoprotein receptor-related protein 1 in inflammation, Curr. Opin. Lipidol. source
- cites [53] Overton, 2007, Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse, Circ. Res. source
- Findingcitation
Cholesterol levels in DKO recipient mice did not decrease after apoE expression.
“As expected, cholesterol levels in DKO recipient mice did not decrease after apoE expression ( 15 ).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [15] Fazio, 2002, Physiological expression of macrophage apoE in the artery wall reduces atherosclerosis in severely hyperlipidemic mice, J. Lipid Res. source
- Premisecitation
At 20 weeks, plaque macrophages are mainly M2.
“We studied lesion development at an early stage (20 weeks), when plaque macrophages are mainly M2.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [19] Khallou-Laschet, 2010, Macrophage plasticity in experimental atherosclerosis, PLoS ONE. source
- Premisecitation
apoE-/- and DKO mice have been reported to develop renal abnormalities that are different from those found in LPG.
“apoE Ϫ / Ϫ and DKO mice have been reported to develop renal abnormalities that are different from those found in LPG (40)(41)(42).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [40] Ishimura, 2009, Lipoprotein glomerulopathy induced by ApoE-Sendai is different from glomerular lesions in aged apoE-deficient mice, Clin. Exp. Nephrol. source
- cites [41] Wen, 2002, Renal injury in apolipoprotein E-deficient mice, Lab. Invest. source
The Abstract reports renal injury in apoE-deficient mice and cites a study of renal injury in double-knockout mice. But the Discussion says that a lesion in the apoE-deficient mice resembles the lipoprotein thrombi of LPG, so this paper does not support a blanket claim that their renal abnormalities differ from those in LPG. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [42] Langheinrich, 2010, Atherosclerosis, inflammation and lipoprotein glomerulopathy in kidneys of apoE-/-/LDL-/- double knockout mice, BMC Nephrol. source
The Results report renal-artery atherosclerosis, perivascular inflammation, and reduced renal vascular volume in double-knockout (DKO) mice—abnormalities beyond the glomerular lipoprotein deposits used to characterize LPG. But the same Results report LPG in 41% of their glomeruli, and the Discussion says apoE-/- mice spontaneously develop LPG. The source therefore does not support a broad distinction between the mice’s renal abnormalities and LPG. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
Macrophage apoE effects manifest as modulation of the macrophage inflammatory response in the atheroma.
“Atherogenesis is infl uenced by macrophage expression of apoE ( 11 ), the effects of which manifest as: 1 ) secretion into the circulation and association with lipoproteins to mediate their hepatic uptake ( 3, 6 ); and 2 ) modulation of the macrophage infl ammatory response in the atheroma ( 16,17 ).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [16] Yancey, 2011, Low-density lipoprotein receptor-related protein 1 prevents early atherosclerosis by limiting lesional apoptosis and inflammatory Ly-6Chigh monocytosis: evidence that the effects are not apolipoprotein E dependent, Circulation. source
- cites [17] Murphy, 2011, ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice, J. Clin. Invest. source
The Discussion reports that Apoe-deficient monocytes were slightly activated and suggests they may be primed to respond to signals within lesions. It does not establish that macrophage apoE modulates the inflammatory response of macrophages in the atheroma; the paper’s demonstrated mechanism centers on stem-cell proliferation and monocyte accumulation. (LLM, conf=0.78)
Experimental — accuracy not yet measured
- Premisecitation
We have previously reported that serum clearance of macrophage apoE is altered in these DKO mice resulting in accumulation of circulating apoE.
“We have previously reported that serum clearance of macrophage apoE is altered in these DKO mice resulting in accumulation of circulating apoE ( 15 ).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [15] Fazio, 2002, Physiological expression of macrophage apoE in the artery wall reduces atherosclerosis in severely hyperlipidemic mice, J. Lipid Res. source
The Results (page unavailable) report that macrophage-derived apoE accumulated in the plasma of apoE/LDLR double-knockout mice after bone marrow transplantation. The paper does not directly report altered serum clearance of macrophage apoE; its discussion of impaired clearance concerns lipoproteins, so the claim’s proposed explanation is not fully supported. (LLM, conf=0.82)
Experimental — accuracy not yet measured
- Findingown data
In apoE-/- recipient mice, apoE Sendai recipients had a lower average glomerular injury score (0.5) compared with GFP- (1 to 2+) and apoE2-recipient mice (2+).
“Our blinded-operator semiquantitative evaluations showed a lower average glomerular injury score in apoE Sendai recipients (average score 0.5 on a 0 to 3+ scale) compared with both GFP-(average score 1 to 2+) and apoE2-recipient mice (average score 2+) ( Table 1 ).”
Quote in the paperSubstantial claim - Findingown data
The M1/M2 ratio in lesional macrophages was similar between groups in apoE-/- recipient mice.
“The M1/M2 ratio in lesional macrophages (arginase II/arginase I in CD68positive cells) was similar between groups (supplementary Fig. IIB).”
Quote in the paperNot a substantial claim - Findingown data
In apoE-/- recipient mice, apoE3- and apoE Sendai-recipient mice had significantly smaller aortic lesions compared with GFP- and apoE2-recipient mice.
“In apoE3-(n = 5) and apoE Sendai -recipient mice (n = 11), lesions were signifi cantly smaller compared with GFP-and apoE2-recipient mice (lesion area 105,095 ± 15,274 m 2 and 124,849 ± 34,696 m 2 , respectively) ( Fig. 3A ).”
Quote in the paperSubstantial claim - Findingown data
In DKO mice, lipid staining showed increased lipid accumulation in glomeruli and tubules of apoE Sendai-recipient mice compared with apoE2-recipient mice.
“Lipid staining showed increased lipid accumulation in the glomeruli and tubules of apoE Sendai -recipient mice compared with apoE2recipient mice (supplementary Table II).”
Quote in the paperSubstantial claim - Findingown data
No renal artery atherosclerosis was seen in any of the groups in apoE-/- recipient mice.
“No renal artery atherosclerosis was seen in any of the groups ( Fig. 4 ).”
Quote in the paperNot a substantial claim - Findingown data
Similar results were found for CCR2-positive cells in the atheroma of DKO mice.
“Similar results were also found in CCR2-positive cells in the atheroma (supplementary Fig. VIA).”
Quote in the paperNot a substantial claim - Findingown data
apoE2, apoE3, and apoE Sendai were expressed in similar levels by the transduced bone marrow cells.
“apoE2, apoE3, and apoE Sendai were expressed in similar levels by the cells”
Quote in the paperSubstantial claim - Findingown data
In DKO mice, apoE Sendai-recipient mice had significantly fewer Ly6C-positive cells in lesions compared with apoE2-recipient mice.
“Lesion composition analyses showed that DKO apoE Sendai -recipient mice also had signifi cantly fewer Ly6C-positive cells (5.5 ± 1.1%) compared with DKO mice recipient of apoE2 (7.8 ± 1.2%) ( Fig. 5B ).”
Quote in the paperSubstantial claim - Findingown data
Similar results were found for CCR2-positive cells in the atheroma of apoE-/- recipient mice.
“Similar results were also found in CCR2-positive cells in the atheroma (supplementary Fig. IIA).”
Quote in the paperNot a substantial claim - Findingown data
No differences were seen in cholesterol efflux from apoE-/- macrophages transduced with apoE2, apoE3, or apoE Sendai.
“No differences were seen in cholesterol effl ux from apoE Ϫ / Ϫ macrophages transduced with apoE2, apoE3, or apoE Sendai (supplementary Fig. IIC).”
Quote in the paperNot a substantial claim - Findingown data
There were no differences in aortic lesion area between apoE3- and apoE Sendai-recipient apoE-/- mice.
“No differences were noted in extent of lesion areas in apoE3 versus apoE Sendai mice ( Fig. 3A ).”
Quote in the paperSubstantial claim - Findingown data
The M1/M2 ratio in lesional macrophages was similar between groups in DKO mice.
“The M1/M2 ratio in lesional macrophages (arginase II/arginase I in CD68positive cells) was similar between groups (supplementary Fig. VIB).”
Quote in the paperNot a substantial claim - Findingown data
In apoE-/- recipient mice, the mean aortic lesion area of apoE2-recipient mice was 23% lower than that of GFP control mice.
“The mean aortic lesion area of apoE2-recipient mice (n = 10) was 23% lower (183,847 ± 44,446 um 2 ) than that of control mice (n = 7) expressing GFP (239,007 ± 69,446 um 2 ).”
Quote in the paperSubstantial claim - Findingown data
In apoE-/- recipient mice, apoE3- and apoE Sendai-recipient mice had significantly fewer Ly6C-positive cells in lesions compared with apoE2-recipient or GFP recipients.
“Lesion composition analyses showed that apoE3-and apoE Sendai -recipient mice also had significantly fewer Ly6C-positive cells (2.3 ± 0.5% and 2.1 ± 0.3%, respectively) compared with apoE2-recipient mice (2.9 ± 0.3%) or GFP recipients (3.6 ± 0.6%), as shown in Fig. 3B .”
Quote in the paperSubstantial claim - Findingown data
In DKO mice, there were no differences in serum cholesterol levels between apoE2- and apoE Sendai-recipient groups.
“As expected, we did not fi nd differences in serum cholesterol levels in either group (supplementary Fig. IVA).”
Quote in the paperSubstantial claim - Findingown data
apoE2-, apoE3-, and apoE Sendai-recipient mice all had significantly lower cholesterol compared with control GFP recipients.
“apoE2-, apoE3-, and apoE Sendai -recipient mice all had signifi cantly lower cholesterol (333 ± 62 mg/dl, 183 ± 62 mg/dl, and 259 ± 41 mg/dl, respectively) compared with control GFP recipients (432 ± 63 mg/dl) ( Fig.2A).”
Quote in the paperSubstantial claim - Findingown data
apoE Sendai produced by macrophages in apoE−/− recipient mice effectively causes clearance of circulating lipoproteins.
“Our results show, for the fi rst time, that apoE Sendai produced by macrophages in apoE Ϫ / Ϫ recipient mice effectively causes clearance of circulating lipoproteins.”
Quote in the paperSubstantial claim - Findingown data
Macrophage apoE Sendai is highly athero-protective compared with macrophage apoE2.
“Our data show that macrophage apoE Sendai is highly athero-protective when compared with macrophage apoE2 and results in decreased lesion size, by 32 and 18% in apoE Ϫ / Ϫ and DKO recipient mice, respectively.”
Quote in the paperSubstantial claim - Findingown data
Macrophage apoE Sendai expression reduces aortic lesion size by 32% compared with apoE2 in apoE−/− recipients.
“Our data show that macrophage apoE Sendai is highly athero-protective when compared with macrophage apoE2 and results in decreased lesion size, by 32 and 18% in apoE Ϫ / Ϫ and DKO recipient mice, respectively.”
Quote in the paperSubstantial claim - Findingown data
Low levels of apoE Sendai decrease atherosclerosis.
“2 ) low levels of apoE Sendai alone are not suffi cient to cause LPG, while they decrease serum cholesterol levels and atherosclerosis;”
Quote in the paperSubstantial claim - Findingown data
Macrophage apoE Sendai reduces lesional accumulation of inflammatory monocytes (Ly6C- or CCR2-positive cells) compared with apoE2.
“In addition, apoE Sendai exerts a local anti-infl ammatory effect in the atheroma with reduced lesional accumulation of infl ammatory monocytes (Ly6C-or CCR2-positive cells) when compared with apoE2.”
Quote in the paperSubstantial claim - Findingown data
apoE Sendai has impaired binding to LRP1.
“We show that apoE Sendai has impaired binding to LRP1 and, as”
Quote in the paperSubstantial claim - Findingown data
Macrophage apoE Sendai expression reduces aortic lesion size by 18% compared with apoE2 in apoE−/−/LDLR−/− (DKO) recipients.
“Our data show that macrophage apoE Sendai is highly athero-protective when compared with macrophage apoE2 and results in decreased lesion size, by 32 and 18% in apoE Ϫ / Ϫ and DKO recipient mice, respectively.”
Quote in the paperSubstantial claim - Findingown data
Macrophage apoE Sendai is as athero-protective as apoE3.
“Although macrophage apoE Sendai is considered an apoE2 mutant (due to a similar charge), it was, in fact, as athero-protective as apoE3.”
Quote in the paperSubstantial claim - Findingown data
apoE3- and apoE Sendai-recipient mice had cholesterol levels significantly lower compared with apoE2 recipients.
“apoE3-and apoE Sendairecipient mice, postBMT, had cholesterol levels signifi cantly lower compared with apoE2 recipients.”
Quote in the paperSubstantial claim - Findingown data
Glomerular lesions compatible with LPG with increased mesangial matrix, extracellular lipid accumulation, and focal mesangiolysis were only observed in apoE−/−/LDLR−/− mice expressing apoE Sendai.
“Glomerular lesions compatible with LPG with increased mesangial matrix, extracellular lipid accumulation, and focal mesangiolysis were only observed in apoE ؊ / ؊ /LDLR ؊ / ؊ mice expressing apoE Sendai .”
Quote in the paperSubstantial claim- Rests on an assumption: The renal lesions observed in apoE Sendai-expressing DKO mice are representative of human lipoprotein glomerulopathy.
- Findingown data
No differences in M1/M2 macrophages were detected among any of the groups despite differences in lesional monocyte composition.
“Despite differences in lesional monocyte composition, we could not detect differences in M1/M2 macrophages among any of the groups.”
Quote in the paperNot a substantial claim - Findingown data
Low levels of apoE Sendai decrease serum cholesterol levels.
“2 ) low levels of apoE Sendai alone are not suffi cient to cause LPG, while they decrease serum cholesterol levels and atherosclerosis;”
Quote in the paperSubstantial claim - Findingown data
No statistical significance was found between apoE3 and apoE Sendai in any of the experiments.
“No statistical signifi cance was found between apoE3 and apoE Sendai in any of the experiments.”
Quote in the paperNot a substantial claim - Findingown data
Eight weeks after BMT, macrophage apoE expression resulted in a decrease in serum cholesterol levels.
“Eight weeks after BMT, macrophage apoE expression resulted in a decrease in serum cholesterol levels.”
Quote in the paperSubstantial claim - Premisecitation
The apoE Sendai protein carries a missense mutation of Arg-to-Pro substitution at position 145 (R145P) within the receptor binding domain of apoE.
“The apoE Sendai protein carries a missense mutation of Arg-to-Pro substitution at position 145 (R145P) within the receptor binding domain of apoE ( 24 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] Saito, 2006, Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases, Am. J. Kidney Dis. source
- Premisecitation
apoE Sendai is more effective than apoE2 in binding to HSPG.
“In addition, apoE Sendai is more effective than apoE2 in binding to HSPG ( 34 ).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [34] Hoffmann, 2001, Diminished LDL receptor and high heparin binding of apolipoprotein E2 Sendai associated with lipoprotein glomerulopathy, J. Am. Soc. Nephrol. source
- Premisecitation
Bone marrow transplantation is a reliable and validated approach to study the effect of changes in macrophage gene expression on atherosclerosis in the mouse.
“Bone marrow transplantation is a reliable and validated approach to study the effect of changes in macrophage gene expression on atherosclerosis in the mouse ( 2,11 ).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [2] Linton, 1999, Macrophages, lipoprotein metabolism, and atherosclerosis: insights from murine bone marrow transplantation studies, Curr. Opin. Lipidol. source
- cites [11] Linton, 1995, Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation, Science. source
- Premisecitation
The pathogenetic role of apoE Sendai in LPG has been proven with the replication of an experimental LPG phenotype in mice after adenovirus-driven expression of apoE Sendai.
“The pathogenetic role of apoE Sendai in LPG has been proven with the replication of an experimental LPG phenotype in mice after adenovirus-driven expression of apoE Sendai ( 30 ).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Ishigaki, 2000, Virus-mediated transduction of apolipoprotein E (ApoE)-sendai develops lipoprotein glomerulopathy in ApoE-deficient mice, J. Biol. Chem. source
- Interpretationown data
Higher levels of apoE Sendai during hyperlipidemia cause a renal phenotype similar to LPG.
“4 ) higher levels of apoE Sendai during hyperlipidemia cause a renal phenotype similar to LPG;”
Quote in the paperSubstantial claim- Rests on an assumption: The renal lesions observed in apoE Sendai-expressing DKO mice are representative of human lipoprotein glomerulopathy.
- Interpretationown data
Low levels of apoE Sendai alone are not sufficient to cause LPG.
“2 ) low levels of apoE Sendai alone are not suffi cient to cause LPG, while they decrease serum cholesterol levels and atherosclerosis;”
Quote in the paperSubstantial claim - Interpretationnone given
Higher levels of apoE Sendai reduce atherosclerosis even when they do not affect serum cholesterol levels.
“3 ) higher levels of apoE Sendai reduce atherosclerosis even when they do not affect serum cholesterol levels;”
Quote in the paperSubstantial claim - Interpretationnone given
This is the first demonstration of an apoprotein variant having opposing effects on vascular and renal homeostasis.
“This is the fi rst demonstration of an apoprotein variant having opposing effects on vascular and renal homeostasis.”
Quote in the paperSubstantial claim - Interpretationreasoning
Expression of apoE Sendai causes LPG via glomerular lipid deposition, not macrophage infiltration.
“5 ) expression of apoE Sendai causes LPG via glomerular lipid deposition, not macrophage infi ltration.”
Quote in the paperSubstantial claim- Rests on an assumption: The renal lesions observed in apoE Sendai-expressing DKO mice are representative of human lipoprotein glomerulopathy.
- Interpretationown data
Macrophage apoE Sendai inhibits atherosclerosis.
“We conclude that macrophage apoE Sendai inhibits atherosclerosis while promoting renal disease, two pathologies that share etiologic factors and treatment approaches.”
- Also stated in: § DISCUSSION · plain
“Thus, macrophage expression of apoE Sendai protects against atherosclerosis while causing lipoprotein glomerulopathy.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Interpretationown data
Macrophage apoE Sendai exerts a local anti-inflammatory effect in the atheroma.
“In addition, apoE Sendai exerts a local anti-infl ammatory effect in the atheroma with reduced lesional accumulation of infl ammatory monocytes (Ly6C-or CCR2-positive cells) when compared with apoE2.”
Quote in the paperSubstantial claim - Premisecitation
Atherogenesis is influenced by macrophage expression of apoE.
“Atherogenesis is infl uenced by macrophage expression of apoE ( 11 ), the effects of which manifest as: 1 ) secretion into the circulation and association with lipoproteins to mediate their hepatic uptake ( 3, 6 ); and 2 ) modulation of the macrophage infl ammatory response in the atheroma ( 16,17 ).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Linton, 1995, Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation, Science. source
- Premisecitation
LPG patients carrying apoE Sendai have higher apoE and cholesterol levels compared with asymptomatic apoE Sendai carriers.
“LPG patients carrying apoE Sendai have higher apoE and cholesterol levels compared with asymptomatic apoE Sendai carriers ( 26 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Hu, 2014, Hereditary features, treatment, and prognosis of the lipoprotein glomerulopathy in patients with the APOE Kyoto mutation, Kidney Int. source
- Interpretationreasoning
The effect of apoE Sendai on lesional monocyte accumulation may explain the changes in lesion size even in the absence of cholesterol differences.
“This effect may explain the changes in lesion size even in the absence of cholesterol differences.”
Quote in the paperSubstantial claim - Interpretationown data
Macrophage expression of apoE Sendai does not convey a particular risk for LPG.
“Our experimental model suggests that: 1 ) apoE Sendai expressed by macrophages does not convey a particular risk for LPG;”
Quote in the paperSubstantial claim - Interpretationown data
Macrophage apoE Sendai promotes renal disease.
“We conclude that macrophage apoE Sendai inhibits atherosclerosis while promoting renal disease, two pathologies that share etiologic factors and treatment approaches.”
- Also stated in: § DISCUSSION · plain
“Thus, macrophage expression of apoE Sendai protects against atherosclerosis while causing lipoprotein glomerulopathy.”
Quote in the paperSubstantial claim- Rests on an assumption: The renal lesions observed in apoE Sendai-expressing DKO mice are representative of human lipoprotein glomerulopathy.
- Also stated in: § DISCUSSION · plain
- Classified as probably not a substantial claim. 17
- May combine two claims. 30
- The quote only partly states this claim. 5
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Macrophage-derived apoE Sendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic miceCommon polymorphisms of human apoE (apoE2, -E3, and -E4) influence lipid metabolism due to differences in receptor binding activity and lipoprotein association preference.
“Common polymorphisms of human apoE (apoE2, -E3, and -E4) infl uence lipid metabolism due to differences in receptor binding activity and lipoprotein association preference (5)(6)(7)(8)(9).”
Quote in the paperNot a substantial claim2 of 5 sources checked- cites [5] Corder, 1993, Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families, Science. source
- cites [6] Mahley, 1999, Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes, J. Lipid Res. source
- cites [7] Mahley, 2009, Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS, J. Lipid Res. source
- cites [8] Weisgraber, 1991, Identification of the disulfide-linked homodimer of apolipoprotein E3 in plasma. Impact on receptor binding activity, J. Biol. Chem. source
- cites [9] Fan, 2007, Impaired secretion of apolipoprotein E2 from macrophages, J. Biol. Chem. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationClinical symptoms of LPG vary from mild proteinuria to nephrotic syndrome and chronic renal failure.
“Clinical symptoms of LPG vary from mild proteinuria to nephrotic syndrome and chronic renal failure ( 20,54,55 ).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [20] Saito, 1997, Abnormal lipid metabolism and renal disorders, Tohoku J. Exp. Med. source
The Hereditary metabolic disorders section (around p. 329) describes lipoprotein glomerulopathy’s renal lesions and other clinical features, but does not give the claimed range from mild proteinuria to nephrotic syndrome and chronic renal failure. Searches for those terms found them elsewhere in the paper, not as a description of lipoprotein glomerulopathy. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [54] Meyrier, 1995, Lipoprotein glomerulopathy: first case in a white European, Nephrol. Dial. Transplant. source
- cites [55] Pasquariello, 2011, Lipoprotein glomerulopathy: first report of 2 not consanguineous Italian men from the same town, J. Nephrol. source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Macrophage-derived apoE Sendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic miceThe atheroprotective role of macrophage apoE has been well documented, with macrophage-derived apoE protecting against atherosclerosis during both early and late plaque development; protection remains even when expressed in low amounts and in the absence of changes in serum lipid levels.
“The atheroprotective role of macrophage apoE has been well documented, with macrophage-derived apoE being shown to protect against atherosclerosis during both early ( 12,13 ) and late plaque development ( 11 ); protection remains even when it is expressed in low amounts ( 14 ) and in the absence of changes in serum lipid levels ( 15 ).”
Quote in the paperNot a substantial claim3 of 5 sources checked- cites [11] Linton, 1995, Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation, Science. source
- cites [12] Bellosta, 1995, Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice, J. Clin. Invest. source
- cites [13] Hasty, 1999, Retroviral gene therapy in ApoE-deficient mice: ApoE expression in the artery wall reduces early foam cell lesion formation, Circulation. source
- cites [14] Yoshida, 2001, Isoform-specific effects of apolipoprotein E on atherogenesis: gene transduction studies in mice, Circulation. source
- cites [15] Fazio, 2002, Physiological expression of macrophage apoE in the artery wall reduces atherosclerosis in severely hyperlipidemic mice, J. Lipid Res. source
May combine two claims.
PremisecitationThrough bone marrow transplantation, the authors produced two types of chimeric mice expressing apoE exclusively from macrophages: apoE-/- mice, whose dyslipidemia is corrected by apoE expression; and apoE-/-/LDLR-/- DKO mice, whose dyslipidemia is not affected by apoE expression.
“Through bone marrow transplantation, we produced two types of chimeric mice expressing apoE exclusively from macrophages: 1 ) apoE Ϫ / Ϫ mice, whose dyslipidemia is corrected by apoE expression; and 2 ) apoE Ϫ / Ϫ /LDLR Ϫ / Ϫ double KO (DKO) mice, whose dyslipidemia is not affected by apoE expression ( 15,37 ).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [15] Fazio, 2002, Physiological expression of macrophage apoE in the artery wall reduces atherosclerosis in severely hyperlipidemic mice, J. Lipid Res. source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [37] Linton, 1998, Hepatic apo E expression is required for remnant lipoprotein clearance in the absence of the low density lipoprotein receptor, J. Clin. Invest. source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Macrophage-derived apoE Sendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic miceAbout 90% of serum apoE is made in the liver and the remainder is produced by macrophages.
“About 90% of serum apoE is made in the liver ( 10 ) and the remainder is produced by macrophages ( 11 ).”
Quote in the paperNot a substantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTwo case studies and one small population study showed that lipid-lowering therapies are linked to improved renal status in LPG patients.
“Two case studies and one small population study showed that lipid-lowering therapies are linked to improved renal status in LPG patients (27)(28)(29).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [27] Hamatani, 2010, Successful treatment of lipoprotein glomerulopathy in a daughter and a mother using niceritrol, Clin. Exp. Nephrol. source
- cites [28] Matsunaga, 2009, Improvement of nephrotic syndrome by intensive lipid-lowering therapy in a patient with lipoprotein glomerulopathy, Clin. Exp. Nephrol. source
- cites [29] Ishibashi, 1994, The two-receptor model of lipoprotein clearance: tests of the hypothesis in “knockout” mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins, Proc. Natl. Acad. Sci. USA. source
The Results and Discussion (page numbers unavailable) examine lipoprotein clearance in knockout mice, not renal outcomes in LPG patients. Searches for LPG, lipid-lowering therapy, renal status, and patient case studies found no passage addressing the claim. (LLM, conf=0.75)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationWe have previously reported intracellular retention of apoE2 in macrophages due to its interaction with LRP1.
“We have previously reported intracellular retention of apoE2 in macrophages due to its interaction with LRP1 ( 9 ).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [9] Fan, 2007, Impaired secretion of apolipoprotein E2 from macrophages, J. Biol. Chem. source
Classified as probably not a substantial claim.
PremisecitationapoE-LRP1 interactions in macrophages control the rate of apoE secretion.
“We previously reported that apoE-LRP1 interactions in macrophages control the rate of apoE secretion ( 51 ).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [51] Yancey, 2010, Macrophage LRP-1 controls plaque cellularity by regulating efferocytosis and Akt activation, Arterioscler. Thromb. Vasc. Biol. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDifferentiation into M1 macrophages in the lesion becomes dominant in more advanced stages (>55 weeks).
“Differentiation into M1 macrophages in the lesion becomes dominant in more advanced stages (>55 weeks) ( 19 ).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [19] Khallou-Laschet, 2010, Macrophage plasticity in experimental atherosclerosis, PLoS ONE. source
The Results section (page not provided) compares 20- and 55-week-old ApoE KO mice, and the Discussion says M1 macrophages prevailed over M2 macrophages as lesions progressed. This supports M1 predominance in advanced lesions, but the paper reports mice at 55 weeks, not >55 weeks, and does not establish differentiation into M1 macrophages as the mechanism. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationIt was previously shown that expression of apoE in DKO model does not reduce serum lipid levels, and that macrophage-expressed apoE can protect against atherosclerosis, even in the absence of cholesterol changes.
“It was previously shown that expression of apoE in this model does not reduce serum lipid levels, and that macrophage-expressed apoE can protect against atherosclerosis, even in the absence of cholesterol changes ( 15,37 ).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [15] Fazio, 2002, Physiological expression of macrophage apoE in the artery wall reduces atherosclerosis in severely hyperlipidemic mice, J. Lipid Res. source
- cites [37] Linton, 1998, Hepatic apo E expression is required for remnant lipoprotein clearance in the absence of the low density lipoprotein receptor, J. Clin. Invest. source
The Results (page unavailable) report that restoring macrophage apoE in mice lacking both apoE and LDLR did not significantly change serum cholesterol or triglycerides. The paper does not report whether that intervention protected those mice against atherosclerosis despite unchanged cholesterol; its References list related atherosclerosis studies but do not establish that part of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataIn DKO mice, no changes were found in the percent of renal macrophages (F4/80-positive cells), and no macrophages were present in either normal (apoE2 recipients) or injured (apoE Sendai recipients) glomeruli.
“Finally, we found no changes in the percent of renal macrophages (F4/80-positive cells), and no macrophages were present in either normal (apoE2 recipients) or injured (apoE Sendai recipients) glomeruli (supplementary Fig. VIIA and B, respectively).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataapoE Sendai is weakly associated with LRP1 and is not retained in macrophages.
“Here, we show that apoE Sendai is weakly associated with LRP1 and is not retained in macrophages.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAn artificial apoE2-R145P mutation has impaired interaction with LRP1 and is not retained by cells, similar to apoE Sendai.
“Figure 1C shows that, similarly to apoE Sendai , the apoE2-R145P artifi cial mutation had impaired interaction with LRP1 and was not retained by the cells.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataDKO apoE Sendai-recipient mice showed lipid thrombi filling the capillary loop.
“Macrophage showed lipid thrombi fi lling the capillary loop, similar to the histological fi nding in human LPG ( Fig. 6 ).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn DKO mice, glomeruli of apoE2-recipient mice had minimal increase in mesangial matrix and a glomerular injury score of 1+, whereas apoE Sendai recipients had smaller glomeruli and increased mesangial matrix with focal mesangiolysis and a glomerular injury score of 2+ to 3.
“Glomeruli of DKO apoE2-recipient mice had minimal increase in mesangial matrix and a glomerular injury score of 1+, whereas DKO apoE Sendai recipients had smaller glomeruli and increased mesangial matrix with focal mesangiolysis ( Fig. 6 ), and a glomerular injury score of 2+ to 3 ( Table 2 ).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn apoE-/- recipient mice, similar amounts and distribution of vacuoles were seen in proximal tubules in all groups, with average injury score 2 to 3+ in GFP recipients and 2+ in apoE2 and apoE Sendai recipients.
“Similar amounts and distribution of vacuoles were seen in the proximal tubules in all groups, with an average injury score of 2 to 3+ in GFP-recipient mice and 2+ in apoE2 and apoE Sendai recipients, as shown in Table 1 .”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataEight weeks after BMT, serum apoE levels in DKO recipients were significantly higher than in apoE-/- recipient mice, both in apoE2- (3.4-fold) and apoE Sendai-recipient mice (2.8-fold).
“Similarly, 8 weeks after BMT, serum apoE levels in DKO recipients were signifi cantly higher compared with apoE Ϫ / Ϫ recipient mice, both in apoE2-(3.4-fold)and apoE Sendai -recipient mice (2.8-fold) (supplementary Fig. IVB).”
Quote in the paperNot a substantial claimMay combine two claims. The quote only partly states this claim.
Findingown dataNo differences were found in the percent of renal macrophages (F4/80-positive cells) in apoE-/- recipient mice, and no macrophages were present in glomeruli in any group.
“No differences were found in the percent of macrophages (F4/80-positive cells) in the kidney and no macrophages were present in glomeruli in any of the groups (supplementary Fig. IIIA and B, respectively).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn DKO mice, both groups showed vacuoles in proximal tubules with average tubular injury score of 2+.
“Both groups showed vacuoles in the proximal tubules, with an average tubular injury score of 2+.”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataGlomerular and tubular lipid accumulation corresponded to injury score in apoE-/- recipient mice.
“Glomerular and tubular lipid distribution (ORO staining) was also assessed, showing lipid accumulation in accordance with the injury score (supplementary Table I).”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataIn apoE-/- recipient mice, none of the glomeruli contained actual LPG-like lesions.
“Although mesangial matrix increase was seen in some glomeruli in all groups, none of the glomeruli contained actual LPG-like lesions ( Fig. 4 ).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMacrophages retain the apoE2 isoform but not apoE3 or apoE Sendai.
“Figure 1C shows that macrophages retain the apoE2 isoform, but not apoE3 and apoE Sendai .”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCholesterol levels of apoE3-recipient mice were lower compared with apoE Sendai, but did not reach statistical significance.
“Cholesterol levels of apoE3-recipient mice were lower compared with apo-E Sendai , but did not reach statistical signifi cance.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Macrophage-derived apoE Sendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic miceapoE on triglyceride-rich lipoproteins binds to LDLR, LRP1, and HSPGs.
“apoE on triglyceride-rich lipoproteins binds to the LDL receptor (LDLR), the LDLR-related protein 1 (LRP1), and heparan sulfate proteoglycans (HSPGs) ( 3,4 ).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Macrophage-derived apoE Sendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic miceHuman apoE is present on nearly all serum lipoproteins and plays a protective role in atherosclerosis by acting both as a ligand for receptor-mediated lipoprotein clearance and as an acceptor for cholesterol exported by peripheral cells.
“Human apoE is present on nearly all serum lipoproteins and plays a protective role in atherosclerosis by acting both as a ligand for receptor-mediated lipoprotein clearance and as an acceptor for cholesterol exported by peripheral cells ( 1,2 ).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSeveral rare apoE mutations have been linked to the development of LPG, with the most common and best characterized being apoE Sendai.
“Several rare apoE mutations have been linked to the development of LPG ( 22 ), with the most common and best characterized being apoE Sendai ( 23 ).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationLPG patients present elevated apoE serum levels and often an abnormal lipid profile compared with control subjects.
“LPG patients present elevated apoE serum levels and often an abnormal lipid profi le compared with control subjects (24)(25)(26).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [24] Saito, 2006, Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases, Am. J. Kidney Dis. source
- cites [25] Saito, 1999, Lipoprotein glomerulopathy: significance of lipoprotein and ultrastructural features, Kidney Int. Suppl. source
- cites [26] Hu, 2014, Hereditary features, treatment, and prognosis of the lipoprotein glomerulopathy in patients with the APOE Kyoto mutation, Kidney Int. source
The quote only partly states this claim.
Interpretationown dataThe lipid thrombi in DKO apoE Sendai recipients are similar to the histological finding in human LPG.
“Macrophage showed lipid thrombi fi lling the capillary loop, similar to the histological fi nding in human LPG ( Fig. 6 ).”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ Macrophage-derived apoE Sendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic miceapoE made by macrophages is secreted into the circulation, where it associates with lipoproteins and mediates their hepatic uptake by the liver.
“apoE made by macrophages is secreted into the circulation, where it associates with lipoproteins and mediates their hepatic uptake by the liver ( 3,6 ).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationapoE was the first apoprotein studied in murine BMT experiments, and has been shown to affect atherosclerosis both by reducing serum lipid levels and by exerting local beneficial effects in the forming atheroma.
“apoE was the fi rst apoprotein studied in murine BMT experiments, and has been shown to affect atherosclerosis both by reducing serum lipid levels ( 11 ) and by exerting local benefi cial effects in the forming atheroma ( 43 ).”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim. May combine two claims.
PremisecitationSeveral very rare apoE mutants are associated with a progressive glomerular disease, termed LPG, with the most common being apoE Sendai.
“Several very rare apoE mutants are associated with a progressive glomerular disease, termed LPG ( 22 ), with the most common being apoE Sendai ( 32 ).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Interpretationown dataMacrophage expression of apoE Sendai reduces arterial wall inflammation, suppresses atherosclerosis, and at the same time induces glomerular deterioration under severe hyperlipidemia.
“Our results support a novel biologic scenario where macrophage expression of apoE Sendai reduces arterial wall infl ammation, suppresses atherosclerosis, and at the same time induces glomerular deterioration under severe hyperlipidemia.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMacrophage expression of apoE influences both serum lipids and atherogenesis.
“Macrophage expression of apoE infl uences both serum lipids and atherogenesis ( 11 ).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Linton, 1995, Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation, Science. source
May combine two claims.
PremisecitationAlthough its mutation is in the receptor binding domain, apoE Sendai is capable of efficient lipoprotein clearance, and its expression decreases serum cholesterol levels in apoE-/- mice.
“Although its mutation is in the receptor binding domain, apoE Sendai is capable of effi cient lipoprotein clearance, and its expression decreases serum cholesterol levels in apoE Ϫ / Ϫ mice ( 30 ).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Ishigaki, 2000, Virus-mediated transduction of apolipoprotein E (ApoE)-sendai develops lipoprotein glomerulopathy in ApoE-deficient mice, J. Biol. Chem. source
May combine two claims.
Interpretationown dataThe results support a scenario where expression of macrophage apoE Sendai protects against atherosclerosis, irrespective of serum lipid changes, while causing glomerular changes compatible with LPG under hyperlipidemic conditions.
“Our results support a scenario where the expression of macrophage apoE Sendai protects against atherosclerosis, irrespective of serum lipid changes, while causing glomerular changes compatible with LPG under hyperlipidemic conditions.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAlthough the apoE Sendai mutation has been directly linked to LPG, the pathogenesis of the disease is not defined.
“Although the apoE Sendai mutation has been directly linked to LPG (30)(31)(32)(33), the pathogenesis of the disease is not defi ned.”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [30] Ishigaki, 2000, Virus-mediated transduction of apolipoprotein E (ApoE)-sendai develops lipoprotein glomerulopathy in ApoE-deficient mice, J. Biol. Chem. source
- cites [31] Matsunaga, 1999, A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy, Kidney Int. source
- cites [32] Oikawa, 1997, Sendai (arginine 145→proline): a new variant associated with lipoprotein glomerulopathy, J. Am. Soc. Nephrol. source
- cites [33] Saito, 2002, Etiological significance of apolipoprotein E mutations in lipoprotein glomerulopathy, Trends Cardiovasc. Med. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLPG patients carrying apoE Sendai may show a lipoprotein profile ranging from near normal to one that resembles type III hyperlipoproteinemia.
“LPG patients carrying apoE Sendai may show a lipoprotein profi le ranging from near normal to one that resembles type III hyperlipoproteinemia (24)(25)(26).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [24] Saito, 2006, Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases, Am. J. Kidney Dis. source
- cites [25] Saito, 1999, Lipoprotein glomerulopathy: significance of lipoprotein and ultrastructural features, Kidney Int. Suppl. source
- cites [26] Hu, 2014, Hereditary features, treatment, and prognosis of the lipoprotein glomerulopathy in patients with the APOE Kyoto mutation, Kidney Int. source
May combine two claims.
PremisecitationLPG recurs in transplanted kidneys, implicating systemic rather than renal factors in the development of the disease.
“LPG recurs in transplanted kidneys, implicating systemic rather than renal factors in the development of the disease ( 21,56 ).”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
Study design and conductown dataThe effect of apoE Sendai on renal pathology under hyperlipidemic conditions was assessed in DKO apoE2- and apoE Sendai-recipient mice by a blinded expert pathologist.
“The effect of apoE Sendai on renal pathology under hyperlipidemic conditions was assessed in DKO apoE2-and apoE Sendai -recipient mice by a blinded expert pathologist, as reported above.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMacrophage apoE effects manifest as secretion into the circulation and association with lipoproteins to mediate their hepatic uptake.
“Atherogenesis is infl uenced by macrophage expression of apoE ( 11 ), the effects of which manifest as: 1 ) secretion into the circulation and association with lipoproteins to mediate their hepatic uptake ( 3, 6 ); and 2 ) modulation of the macrophage infl ammatory response in the atheroma ( 16,17 ).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationapoE Sendai has functional characteristics distinct from other apoE mutants, such as increased binding to HSPGs and reduced binding to the LDLR.
“apoE Sendai has functional characteristics distinct from other apoE mutants, such as increased binding to HSPGs and reduced binding to the LDLR ( 30 ).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Ishigaki, 2000, Virus-mediated transduction of apolipoprotein E (ApoE)-sendai develops lipoprotein glomerulopathy in ApoE-deficient mice, J. Biol. Chem. source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAll animal experiments were carried out in compliance with National Institutes of Health guidelines and were approved by the Institutional Animal Care and Use Committees of Vanderbilt University and Oregon Health and Science University.
“All animal experiments were carried out in compliance with National Institutes of Health guidelines and were approved by the Institutional Animal Care and Use Committees of Vanderbilt University and Oregon Health and Science University.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationnone givenThe two pathologies caused by macrophage apoE Sendai, atherosclerosis and renal disease, share etiologic factors and treatment approaches.
“two pathologies that share etiologic factors and treatment approaches.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The renal lesions observed in apoE Sendai-expressing DKO mice are representative of human lipoprotein glomerulopathy.
“Glomerular lesions compatible with LPG with increased mesangial matrix, extracellular lipid accumulation, and focal mesangiolysis were only observed in apoE ؊ / ؊ /LDLR ؊ / ؊ mice expressing apoE Sendai .”
“4 ) higher levels of apoE Sendai during hyperlipidemia cause a renal phenotype similar to LPG;”
The paper relies on this without support.
apoE Sendai causes LPG in humans and transgenic mice.
“apoE Sendai (Arg145Pro), a rare mutant based on the apoE3 sequence carrying an apoE2 charge, causes LPG in humans and transgenic mice, but its effects on the artery wall are unknown.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A majority of animal experiments suggested that human apoE3 could postpone the progression of atherosclerosis by decreasing serum total cholesterol or changing the inflammatory cell composition of the local plaque.
“A majority of animal experiments suggested that human apoE3 could postpone the progression of atherosclerosis by decreasing serum total cholesterol or changing the inflammatory cell composition of the local plaque [19–21].”
From Lipoprotein glomerulopathy induced by ApoE Kyoto mutation in ApoE-deficient mice (2021) · cites this paper as [19]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
FPLC fraction assignments differ between Methods and Fig. 2
MinorThe Methods assign fractions 15-19 to VLDLs/chylomicrons and 27-33 to HDLs, whereas the Fig. 2 caption assigns fractions 12-18 and 28-34 to those groups, respectively. The stated boundaries for LDL-containing and lipoprotein-deficient fractions also differ.
“Fractions 15-19 were VLDLs and chylomicrons; fractions 20-26 were IDLs, LDLs, and large HDLs; fractions 27-33 were HDLs; and fractions 34-40 were lipoprotein-defi cient serum.”
“Fractions 12-18, VLDLs/chylomicron remnants; fractions 18-27, LDLs; fractions 28-34, HDLs, and fractions 35-40, lipoprotein-defi cient serum.”
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Tavori, H., Giunzioni, I., Predazzi, I. M., Plubell, D. L., Shivinsky, A., Miles, J., DeVay, R. M., Hong, L., Rashid, S., Linton, M. F., et al. (2016) · Cardiovascular Research · doi:10.1093/cvr/cvw053 · Cited by 114 · see citing works
Self-citationApolipoprotein E–related glomerular disorders
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Apolipoprotein E and Atherosclerosis
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Lipoprotein glomerulopathy induced by ApoE Kyoto mutation in ApoE-deficient mice
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Wu, H., Yang, J., Liu, Y.-Q., Lei, S., Yang, M., Yang, Z., Yang, Y., & Hu, Z. (2021) · Figshare · doi:10.6084/m9.figshare.14167912
Wu, H., Yang, J., Liu, Y.-Q., Lei, S., Yang, M., Yang, Z., Yang, Y., & Hu, Z. (2021) · Figshare · doi:10.6084/m9.figshare.14167909
An Updated Review and Meta Analysis of Lipoprotein Glomerulopathy
Li, M.-S., Li, Y., Liu, Y., Zhou, X.-J., & Zhang, H. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.905007 · Cited by 25 · see citing works
- Authors
- Tavori, H., Fan, D., Giunzioni, I., Zhu, L., Linton, M. F., Fogo, A. B., & Fazio, S.
- Affiliations
- Oregon Health & Science University (US)
- University of South Carolina (US)
- Vanderbilt University Medical Center (US)
- Corresponding author
- Fazio, Sergio
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 55
- Issue
- 10
- Pages
- 2073-2081
- ISSN
- 0022-2275 (ISSN-L)
- PMC
- PMC4174000
- OpenAlex
- W2128610687
- Cited by
- 10
- References
- 56
- Citations by year
- 2022: 1 · 2021: 4 · 2019: 1 · 2018: 1 · 2016: 1 · 2015: 2
- FWCI
- 0.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL057986)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056942, DK56942)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, macrophages, atherosclerosis, lipoprotein glomerulopathy, hyperlipidemia, LDL receptor deficiency, bone marrow transplantation, vascular inflammation, mesangial matrix, lipid accumulation, mesangiolysis
- MeSH terms
- Animals, Apolipoproteins E, Glomerular Mesangium, Hyperlipidemias, Inflammation, Kidney Diseases, Macrophages, Receptors, LDL, Mice, Knockout, Atherosclerosis, Mice
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-31.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.
Cited sources are checked by gpt-6-sol.
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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