Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4
Open accessAbstract
We have used adenovirus-mediated gene transfer in apolipoprotein (apo)E(-/-) mice to elucidate the molecular etiology of a dominant form of type III hyperlipoproteinemia (HLP) caused by the R142C substitution in apoE4. It was found that low doses of adenovirus expressing apoE4 cleared cholesterol, whereas comparable doses of apoE4[R142C] greatly increased plasma cholesterol, triglyceride, and apoE levels, caused accumulation of apoE in VLDL/IDL/LDL region, and promoted the formation of discoidal HDL. Co-expression of apoE4[R142C] with lecithin cholesterol acyltransferase (LCAT) or lipoprotein lipase (LPL) in apoE(-/-) mice partially corrected the apoE4[R142C]-induced dyslipidemia. High doses of C-terminally truncated apoE4[R142C]-202 partially cleared cholesterol in apoE(-/-) mice and promoted formation of discoidal HDL. The findings establish that apoE4[R142C] causes accumulation of apoE in VLDL/IDL/LDL region and affects in vivo the activity of LCAT and LPL, the maturation of HDL, and the clearance of triglyceride-rich lipoproteins. The prevention of apoE4[R142C]-induced dyslipidemia by deletion of the 203-299 residues suggests that, in the full-length protein, the R142C substitution may have altered the conformation of apoE bound to VLDL/IDL/LDL in ways that prevent triglyceride hydrolysis, cholesterol esterification, and receptor-mediated clearance in vivo.
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Written from the paper’s full text.
TL;DR
In apoE−/− mice, adenovirus-expressed apoE4[R142C] caused severe hypercholesterolemia, hypertriglyceridemia, high plasma apoE, apoE accumulation in VLDL/IDL/LDL, and discoidal HDL, whereas wild-type apoE4 cleared cholesterol. The phenotype was partially corrected by LCAT or LPL co-expression and prevented by deleting C-terminal residues 203–299, implicating altered apoE conformation and impaired LPL/LCAT/receptor-mediated clearance.
Key findings
- Low-dose (5 × 10⁸ pfu) apoE4 cleared cholesterol, did not affect plasma triglycerides, and caused only a small apoE increase; the same dose of apoE4[R142C] increased plasma cholesterol over four days, induced severe hypertriglyceridemia, and raised plasma apoE, with no statistically different hepatic apoE mRNA levels.
- In apoE4[R142C]-expressing mice, over 90% of cholesterol was in VLDL/IDL and HDL cholesterol was unesterified, versus over 85% of cholesterol in HDL and mostly esterified with wild-type apoE4; apoE accumulated in VLDL/IDL/LDL, shifted toward HDL2, and showed a 7.5-fold increase versus wild-type apoE4 in plasma.
- Co-expression with LCAT did not correct hypercholesterolemia but significantly decreased plasma triglycerides and increased plasma apoE on days 2–4; co-expression with LPL partially corrected hypertriglyceridemia and hypercholesterolemia on days 2–4 and significantly decreased plasma apoE on day 2.
- Truncated apoE4[R142C]-202 (2 or 3.5 × 10⁹ pfu) partially cleared cholesterol without inducing hypertriglyceridemia, reducing cholesterol to approximately 250 mg/dl on day 1; wild-type apoE4-202 reduced cholesterol to approximately 100 mg/dl, and triglyceride levels were 35–70 mg/dl.
Methods
- Adenovirus-mediated gene transfer in male and female apoE−/− mice 8–10 weeks old, with groups of four or more mice injected with 0.5–3.5 × 10⁹ pfu of adenoviruses expressing wild-type or mutant human apoE forms; blood was collected after a 4 h fast before injection and on days 1–4 postinfection.
- Plasma lipids were measured by FPLC and spectrophotometry; plasma apoE by sandwich ELISA; hepatic human apoE mRNA by quantitative PCR; lipoprotein distribution by KBr density gradient ultracentrifugation and SDS-PAGE; HDL morphology by electron microscopy; HDL subfractions by non-denaturing two-dimensional electrophoresis.
- Data are presented as mean ± SD, with statistically significant differences between two groups determined by Student’s t-test with unequal variance; figures report significance at P < 0.02.
Limitations
- The paper does not state a formal limitations section; the authors note that human subjects or experimental animals homozygous for the R142C mutation have not been studied previously.
- Evident from the text: conclusions rely on acute adenovirus-mediated overexpression in apoE−/− mice over four days, not on human patients or long-term physiology.
- Evident from the text: LCAT or LPL co-expression only partially corrected the dyslipidemia, and the truncated apoE4[R142C]-202 experiments may not fully model the full-length mutant protein in humans.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
16 of 40 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Sequence analysis identified an R142C substitution in the ε4 allele (Arg112 Cys142 Arg158).
“Sequence analysis identifi ed an R142C substitution in the 4 allele (Arg112 Cys142 Arg158) ( 29 ).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [29] Rall, 1989, Type III hyperlipoproteinemia associated with apolipoprotein E phenotype E3/3. Structure and genetics of an apolipoprotein E3 variant, J. Clin. Invest. source
The Results (p. 1097) report sequencing an allele encoding Arg112 and Cys142; the paper also identifies Arg158 in its analysis of the variant. But it calls the observed product an apo E3 variant. The Discussion says it is likely, rather than established, that the variant arose through a mutation in an apo E4 allele, so the claim overstates its identification as an ε4 allele. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
The β-VLDL obtained from these mice was cleared at a significantly slower rate than normal mouse VLDL.
“The  -VLDL obtained from these mice was cleared at a significantly slower rate than normal mouse VLDL ( 30 ).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [30] Fazio, 1993, Type III hyperlipoproteinemic phenotype in transgenic mice expressing dysfunctional apolipoprotein E, J. Clin. Invest. source
- Interpretationcitation
The insufficiency of LPL appears to result from inhibition of this enzyme by apoE, which accumulates in VLDL/IDL/LDL-size lipoprotein particles.
“As reported previously ( 36,37 ), the insuffi ciency of LPL appears to result from inhibition of this enzyme by apoE, which accumulates in VLDL/IDL/LDL-size lipoprotein particles.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [36] Jong, 1997, Nascent very-low-density lipoprotein triacylglycerol hydrolysis by lipoprotein lipase is inhibited by apolipoprotein E in a dose-dependent manner, Biochem. J. source
Table 4 and the Discussion show that adding apoE to nascent VLDL inhibits LPL-mediated triacylglycerol hydrolysis in vitro. The Discussion treats the physiological importance of this inhibition as unresolved; it does not establish that apoE accumulation in VLDL/IDL/LDL-size particles causes LPL insufficiency. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [37] Rensen, 1996, Apolipoprotein E effectively inhibits lipoprotein lipase-mediated lipolysis of chylomicron-like triglyceride-rich lipid emulsions in vitro and in vivo, J. Biol. Chem. source
The paper concludes that apoE inhibits LPL-mediated hydrolysis of chylomicron-like emulsion triglycerides in vitro and in vivo. It also says VLDL and chylomicrons become enriched in apoE during lipolysis, but the cited passages do not establish that apoE accumulation in VLDL/IDL/LDL-size particles causes the particular LPL insufficiency described here. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Premisecitation
The contribution of other members of the LDL-receptor family and heparan sulfate proteoglycans to the clearance of apoE-containing lipoprotein remnants in mice may be limited.
“and that the contribution of the other members of the LDL-receptor family and heparan sulfate proteoglycans (HSPG) may be limited ( 49 ).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [49] Kypreos, 2006, LDL receptor deficiency or apoE mutations prevent remnant clearance and induce hypertriglyceridemia in mice, J. Lipid Res. source
- Premisecitation
Heterozygous patients with a dominant form of type III HLP carrying the ε3 allele and a mutant allele were described in 1983.
“Heterozygous patients with a dominant form of type III HLP carrying the 3 allele and a mutant allele were described in 1983 ( 28 ).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [28] Havel, 1983, Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3, J. Clin. Invest. source
The Introduction (page not provided) describes a 1983 study of familial dysbetalipoproteinemia with an E3/3 phenotype that appeared across three generations and had characteristics of a dominant trait. The discussion (page not provided) considers a normal E-3 allele in affected children but also raises the possibility of two functionally defective E-3 alleles. It does not establish that the patients were heterozygous for an ε3 allele and a mutant allele. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
Abnormal lipid and lipoprotein phenotypes have been observed in mice as a result of overexpression of the endogenous mouse apoE.
“lipoprotein phenotypes have been observed in mice as a result of overexpression of the endogenous mouse apoE ( 33 ).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [33] Drosatos, 2007, A dominant negative form of the transcription factor c-Jun affects genes that have opposing effects on lipid homeostasis in mice, J. Biol. Chem. source
- Interpretationcitation
The phenotype generated by expression of the apoE4[R142C] mutant in apoE-/- mice is much more severe than in transgenic mice that also express the endogenous apoE gene.
“The phenotype generated by expression of the apoE4[R142C] mutant in apoE Ϫ / Ϫ mice is much more severe than in transgenic mice that also express the endogenous apoE gene ( 30 ).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [30] Fazio, 1993, Type III hyperlipoproteinemic phenotype in transgenic mice expressing dysfunctional apolipoprotein E, J. Clin. Invest. source
The Results describe transgenic mice expressing the mutant alongside endogenous mouse apoE. They compare those mice with apoE-null mice, but do not report mice expressing the mutant on an apoE−/− background. The claimed severity comparison between mutant-expressing mice with and without endogenous apoE is therefore not established. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Premisecitation
The LDL receptor alone can account for the clearance of apoE-containing lipoprotein remnants in mice.
“The same study also showed that the LDL receptor alone can account for the clearance of apoE-containing lipoprotein remnants in mice”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [49] Kypreos, 2006, LDL receptor deficiency or apoE mutations prevent remnant clearance and induce hypertriglyceridemia in mice, J. Lipid Res. source
- Premisecitation
Defective recognition of apoE-containing lipoproteins due to mutations in apoE or LDL receptor deficiency may increase the sensitivity and severity of hypertriglyceridemia.
“We recently showed that defective recognition of apoEcontaining lipoproteins, either due to mutations in apoE or defi ciency in the LDL receptor, may increase the sensitivity and severity of hypertriglyceridemia ( 49 ).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [49] Kypreos, 2006, LDL receptor deficiency or apoE mutations prevent remnant clearance and induce hypertriglyceridemia in mice, J. Lipid Res. source
The concluding passage in the section on defective apoE–LDL receptor interactions states that either LDL receptor defects or apoE mutations increase the sensitivity and severity of hypertriglyceridemia. The finding is specifically for apoE-induced hypertriglyceridemia in mice; the citing sentence omits those limits. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Findingown data
The HDL cholesterol of HDL isolated by FPLC from mice co-expressing apoE4[R142C] and LPL, as well as that of control mice expressing apoE4[R142C] and GFP, was unesterified.
“The HDL cholesterol of HDL isolated by FPLC from mice co-expressing apoE4[R142C] and LPL, as well as that of the control mice expressing apoE4[R142C] and GFP, was unesterifi ed ( Fig. 5E, F ).”
Quote in the paperNot a substantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
Human apoE mRNA levels of mice co-infected with adenovirus expressing apoE4[R142C] and GFP and mice co-infected with adenoviruses expressing apoE4[R142C] and LPL were not statistically different.
“Real-time qRT-PCR analysis showed that the human apoE mRNA levels of mice co-infected with adenovirus expressing apoE4[R142C] and GFP and mice co-infected with adenoviruses expressing apoE4[R142C] and LPL were not statistically different ( Fig. 5D ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
ApoE4[R142C] expressing adenovirus formed a mixture of spherical and discoidal HDL particles.
“apoE4[R142C] expressing adenovirus formed a mixture of spherical and discoidal HDL particles ( Fig. 2D ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
There was a 7.5-fold increase of the mutant compared with the WT apoE4 in plasma.
“Overall, there was a 7.5-fold increase of the mutant compared with the WT apoE4 in plasma.”
Quote in the paperNot a substantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
When mice were infected with a low dose of apoE4-expressing adenovirus (5 × 10^8 pfu), most of the apoE was found in the HDL3 region.
“When the mice were infected with a low dose of apoE4-expressing adenovirus (5 × 10 8 pfu), most of the apoE was found in the HDL3 region.”
Quote in the paperNot a substantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
Electron microscopy of fractions 6 and 7 showed that apoE-/- mice infected with a low dose (5 × 10^8 pfu) of apoE4 expressing adenovirus formed spherical HDL.
“Electron microscopy of fractions 6 and 7 ( Fig. 2A, B ), which correspond to the HDL3 region, showed that apoE Ϫ / Ϫ mice infected with a low dose (5 × 10 8 pfu) of apoE4 expressing adenovirus formed spherical HDL ( Fig. 2C )”
Quote in the paperNot a substantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
LCAT treatment did not correct the hypercholesterolemia on days 1-4 postinfection in mice expressing apoE4[R142C] plus LCAT compared with mice expressing apoE4[R142C] plus GFP.
“This analysis showed that the LCAT treatment did not correct the hypercholesterolemia, on days 1-4 postinfection, of mice expressing apoE4[R142C] plus LCAT compared with mice expressing apoE4[R142C] plus GFP ( Fig. 3A ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
The increase in triglyceride levels correlated with parallel increases in plasma apoE levels in apoE-/- mice expressing apoE4[R142C].
“The increase in triglyceride levels correlated with parallel increases in plasma apoE levels ( Fig. 1C ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
Hepatic apoE4 and apoE4[R142C] mRNA levels four days postinfection were not statistically different.
“Real-time qRT-PCR analysis showed that the hepatic apoE4 and apoE4[R142C] mRNA four days postinfection were not statistically different ( Fig. 1D ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
As the human apoE levels increase, the mouse apoA-I levels decrease.
“Fig. 2A and 2B also indicate that as the human apoE levels increase, the mouse apoA-I levels decrease.”
Quote in the paperNot a substantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
Hypertriglyceridemia and hypercholesterolemia on days 2-4 were significantly decreased in mice co-expressing apoE4[R142C] and LPL compared with mice co-expressing apoE4[R142C] and GFP.
“However hypertriglyceridemia and hypercholesterolemia on days 2-4 was signifi cantly decreased in mice that were co-expressing apoE4[R142C] and LPL compared with mice that were co-expressing apoE4[R142C] and GFP ( Fig. 5B ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
Plasma apoE levels decreased significantly on day 2 following LPL treatment.
“Plasma apoE levels decreased significantly on day 2 following LPL treatment ( Fig. 5C ).”
Quote in the paperNot a substantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
Removal of the carboxy terminal segment of the apoE4[R142C] mutant protein does not induce hypertriglyceridemia.
“Removal of the carboxy terminal segment of the mutant protein promotes partial clearance of lipoprotein remnants and does not induce hypertriglyceridemia.”
- Also stated in: § Gene transfer studies of the apoE4[R142C] mutant in E · plain
“high levels of expression of the truncated apoE4[R142C]-202 form partially corrected the high cholesterol levels of apoE Ϫ / Ϫ mice without induction of hypertriglyceridemia”
Quote in the paperSubstantial claim - Also stated in: § Gene transfer studies of the apoE4[R142C] mutant in E · plain
- Findingown data
Removal of the carboxy terminal segment of the apoE4[R142C] mutant protein promotes partial clearance of lipoprotein remnants.
“Removal of the carboxy terminal segment of the mutant protein promotes partial clearance of lipoprotein remnants and does not induce hypertriglyceridemia.”
- Also stated in: § Gene transfer studies of the apoE4[R142C] mutant in E · plain
“promotes clearance of the lipoprotein remnants.”
Quote in the paperSubstantial claim - Also stated in: § Gene transfer studies of the apoE4[R142C] mutant in E · plain
- Findingown data
Density gradient ultracentrifugation and SDS-PAGE showed a reduction of apoE levels in the VLDL/IDL/LDL region in mice expressing apoE4[R142C] and LPL compared with mice expressing apoE4[R142C] and GFP.
“Density gradient ultracentrifugation of the plasma of infected mice and SDS-PAGE analysis of the resulting fractions showed a reduction of the apoE levels in the VLDL/ IDL/LDL region in mice expressing apoE4[R142C] and LPL, compared with mice expressing apoE4[R142C] and GFP ( Fig. 6A , B ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
High doses of C-terminally truncated apoE4[R142C]-202 promoted formation of discoidal HDL.
“High doses of C-terminally truncated apoE4[R142C]-202 partially cleared cholesterol in apoE ؊ / ؊ mice and promoted formation of discoidal HDL.”
Quote in the paperNot a substantial claim - Findingown data
Comparable doses of apoE4[R142C] greatly increased plasma apoE levels.
“whereas comparable doses of apoE4[R142C] greatly increased plasma cholesterol, triglyceride, and apoE levels”
Quote in the paperSubstantial claim - Findingown data
Hepatic apoE mRNA levels of mice infected with 3.5 × 10^9 pfu of adenoviruses expressing apoE4[R142C]-202 were lower than in mice infected with the same dose of adenoviruses expressing apoE4-202.
“In addition, the hepatic apoE mRNA levels of mice infected with 3.5 × 10 9 pfu of adenoviruses expressing apoE4[R142C]-202 were lower than in mice infected with the same dose of adenoviruses expressing apoE4-202 ( Fig. 7C ).”
Quote in the paperNot a substantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
Low doses of adenovirus expressing apoE4 cleared cholesterol in apoE-/- mice.
“It was found that low doses of adenovirus expressing apoE4 cleared cholesterol”
Quote in the paperSubstantial claim - Findingown data
Comparable doses of apoE4[R142C] greatly increased plasma cholesterol levels.
“whereas comparable doses of apoE4[R142C] greatly increased plasma cholesterol, triglyceride, and apoE levels”
Quote in the paperSubstantial claim - Findingown data
ApoE4[R142C] promotes the formation of discoidal HDL.
“and promoted the formation of discoidal HDL.”
Quote in the paperSubstantial claim - Findingown data
High levels of expression of the truncated apoE4[R142C]-202 form partially corrected the high cholesterol levels of apoE-/- mice.
“The present study showed that, in contrast to the fulllength mutant protein, high levels of expression of the truncated apoE4[R142C]-202 form partially corrected the high cholesterol levels of apoE Ϫ / Ϫ mice without induction of hypertriglyceridemia”
- Also stated in: § Gene transfer studies of the apoE4[R142C] mutant in E · plain
“High doses of C-terminally truncated apoE4[R142C]-202 partially cleared cholesterol in apoE ؊ / ؊ mice and promoted formation of discoidal HDL.”
Quote in the paperSubstantial claim - Also stated in: § Gene transfer studies of the apoE4[R142C] mutant in E · plain
- Findingown data
The exaggerated phenotype in mice expressing apoE4[R142C]-202 occurs despite the fact that the levels of expression of apoE4[R142C]-202 are lower than those of WT apoE4-202.
“This exaggerated phenotype occurs despite the fact that the levels of expression of apoE4[R142C]-202 are lower than those of the WT apoE4-202 ( Fig. 7C ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
Hepatic human apoE mRNA levels of mice infected with 2 × 10^9 pfu of adenoviruses expressing apoE4[R142C]-202 or apoE4-202 were comparable.
“Real-time qRT-PCR analysis of human apoE mRNA showed that the hepatic human apoE mRNA levels of mice infected with 2 × 10 9 pfu of adenoviruses expressing apoE4[R142C]-202 or apoE4-202 were comparable ( Fig. 7C ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
Plasma apoE levels were significantly lower in mice expressing the WT compared with the mutant truncated apoE form.
“Plasma apoE levels were signifi cantly lower in mice expressing the WT compared with the mutant truncated apoE form ( Fig. 7D ).”
Quote in the paperNot a substantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
Comparable doses of apoE4[R142C] greatly increased plasma triglyceride levels.
“whereas comparable doses of apoE4[R142C] greatly increased plasma cholesterol, triglyceride, and apoE levels”
Quote in the paperSubstantial claim - Findingown data
Electron microscopy showed that plasma of apoE-/- mice co-infected with adenovirus expressing apoE4[R142C] with either GFP or LPL contains a mixture of discoidal and spherical particles.
“Electron microscopy of HDL fractions 5 and 6 ( Fig. 6A, B ) shows that the plasma of apoE Ϫ / Ϫ mice co-infected with adenovirus expressing apoE4[R142C] with either GFP or LPL contains a mixture of discoidal and spherical particles ( Fig. 6C, D ).”
Quote in the paperNot a substantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Findingown data
ApoE4[R142C] causes accumulation of apoE in the VLDL/IDL/LDL region.
“caused accumulation of apoE in VLDL/IDL/LDL region”
- Also stated in: § Gene transfer studies of the apoE4[R142C] mutant in E · boosted
“The fi ndings establish that apoE4[R142C] causes accumulation of apoE in VLDL/IDL/LDL region”
Quote in the paperSubstantial claim - Also stated in: § Gene transfer studies of the apoE4[R142C] mutant in E · boosted
- Findingown data
Full-length apoE4[R142C], despite its abundance in plasma, cannot promote receptor-mediated clearance of apoE-containing lipoproteins in vivo.
“Our data indicate that full-length apoE4[R142C], despite its abundance in plasma, cannot promote receptor-mediated clearance of apoE-containing lipoproteins in vivo.”
Quote in the paperSubstantial claim - Interpretationown data
The differences in plasma cholesterol, triglyceride, and apoE levels, the inhibition of esterification of cholesterol, and the formation of discoidal HDL are not the result of different levels of gene expression of wild-type apoE4 and apoE4[R142C] but reflect alterations in the properties of the apoE[R142C] mutant.
“Together, the data in Figs. 1 and 2 establish that the differences in plasma cholesterol, triglyceride, and apoE levels, the inhibition of esterifi cation of cholesterol, and the formation of discoidal HDL are not the result of different levels of gene expression of the wild-type apoE4 and the apoE4[R142C] but, rather, refl ect alterations in the properties of the apoE[R142C] mutant.”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Premisecitation§ Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4
A variety of rare mutations in the 136-147 region of apoE are associated with a dominant mode of inheritance of type III HLP that is expressed at an early age.
“A variety of rare mutations in the 136-147 region of apoE are associated with a dominant mode of inheritance of type III HLP that is expressed at an early age ( 7,8,12,13 ).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [7] Mahley, 2001, Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism
Not checked in the free run.
- cites [8] Rall, 1992, The role of apolipoprotein E genetic variants in lipoprotein disorders, J. Intern. Med. source
- cites [12] Zannis, 1993, Genetic mutations affecting human lipoproteins, their receptors, and their enzymes, Adv. Hum. Genet. source
- cites [13] Horie, 1992, The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia, J. Biol. Chem. source
- Interpretationown data
ApoE4[R142C]202 lacking residues 203-299 is recognized to some extent by the LDL receptor in vivo.
“indicating that apoE4[R142C]202 that lacks residues 203-299 is recognized to some extent by the LDL receptor in vivo.”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Interpretationreasoning
The observed dyslipidemia in this study cannot be attributed to abnormal interactions of the human apoE with the mouse apolipoproteins.
“Thus the observed dyslipidemia in this study cannot be attributed to abnormal interactions of the human apoE with the mouse apolipoproteins.”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Premisecitation
DMPC proteoliposomes containing the R142C variant expressed in bacteria had reduced binding affinity for the LDL receptor, a receptor blocking monoclonal antibody, and heparin based on competition experiments.
“DMPC proteoliposomes containing the R142C variant expressed in bacteria had reduced binding affi nity for the LDL receptor, a receptor blocking monoclonal antibody, and heparin based on competition experiments ( 13 ).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Horie, 1992, The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia, J. Biol. Chem. source
- Interpretationreasoning
The dyslipidemia induced by E4[R142C] in mice and possibly human patients carrying this mutation is most likely brought about by an altered conformation of the mutant protein bound to VLDL/IDL/LDL particles that impedes the clearance of triglyceride-rich lipoproteins.
“Combined with previous studies, our data indicate that the dyslipidemia induced by E4[R142C] in mice and possibly human patients carrying this mutation is most likely brought about by an altered conformation of the mutant protein bound to the VLDL/IDL/LDL particles that impedes the clearance of triglyceride-rich lipoproteins.”
Quote in the paperSubstantial claim - Interpretationown data
The increased apoE levels are also associated with defective conversion from the discoidal to spherical HDL.
“The increased apoE levels are also associated with defective conversion from the discoidal to spherical HDL.”
Quote in the paperNot a substantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Interpretationcitation
The findings are consistent with the previously reported LDL receptor-binding ability of proteoliposomes containing truncated apoE-184 or apoE-191.
“They are also consistent with the previously reported LDL receptorbinding ability of proteoliposomes containing truncated apoE-184 or apoE-191 ( 51 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [51] Lalazar, 1989, Human apolipoprotein E. Receptor binding activity of truncated variants with carboxyl-terminal deletions, J. Biol. Chem. source
- Interpretationcitation
The findings of truncated apoE4[R142C]-202 are consistent with previous studies involving other truncated apoE forms.
“These fi ndings are consistent with previous studies involving other truncated apoE forms ( 50 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50] Zannis, 2004, Probing the pathways of chylomicron and HDL metabolism using adenovirus-mediated gene transfer, Curr. Opin. Lipidol. source
- Interpretationreasoning
The insufficiency in LCAT may be explained by fast catabolism by the kidney of LCAT bound to discoidal HDL particles that are formed in the plasma of mice expressing apoE4[R142C].
“The insuffi ciency in LCAT may be explained by fast catabolism by the kidney of LCAT bound to discoidal HDL particles that are formed in the plasma of mice expressing apoE4[R142C].”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Premisecitation
The product of the mutant allele predominated in the plasma of the affected subjects by 3:1 compared with the product of the normal ε3 allele.
“The product of the mutant allele predominated in the plasma of the affected subjects by 3:1 compared with the product of the normal 3 allele ( 13 ).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Horie, 1992, The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia, J. Biol. Chem. source
- Interpretationown data
The truncated apoE4[R142C]-202 form does not inhibit lipolysis.
“indicating that it does not inhibit lipolysis and promotes clearance of the lipoprotein remnants.”
Quote in the paperSubstantial claim - Premisecitation
Several transgenic mouse lines expressing the apoE4[R142C] mutant have been generated and studied.
“Several transgenic mouse lines expressing the apoE4[R142C] mutant have been generated and studied.These lines expressed the mutant apoE allele as well as their endogenous mouse apoE gene (30)(31)(32).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (30)(31)(32)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
The increased free cholesterol in VLDL and shoulder formation explains the partial clearance of cholesterol observed in E-/- mice on days 2-4 postinfection with high doses of adenoviruses expressing apoE4[R142C]-202.
“This fi nding explains the partial clearance of cholesterol observed in E Ϫ / Ϫ mice on days 2-4 postinfection with high doses of the adenoviruses expressing apoE4[R142C]-202 observed ( Fig. 7A, B ).”
Quote in the paperSubstantial claim - Interpretationown data
The decrease in CE/TC ratio of VLDL and HDL observed suggested inability of LCAT to esterify the cholesterol of these lipoprotein fractions.
“The decrease in CE/TC ratio of VLDL and HDL observed ( Fig. 1F ) suggested inability of LCAT to esterify the cholesterol of these lipoprotein fractions.”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Interpretationown data
The ability of excess LPL to partially correct the dyslipidemia induced by apoE4[R142C] suggests that the activity of LPL rather than apoCII may be rate limiting for the clearance of VLDL/IDL/LDL triglycerides.
“As observed in this study, the ability of excess LPL to partially correct the dyslipidemia induced by apoE4[R142C] suggests that the activity of LPL rather than apoCII may be rate limiting for the clearance of VLDL/IDL/LDL triglycerides.”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Interpretationown data
The mutant protein has a dominant effect in the clearance of lipoprotein remnants.
“The accumulation of triglycerides in E Ϫ / Ϫ mice that received the adenovirus expressing apoE4[R142C] ( Fig. 1B ) suggest that the mutant protein has a dominant effect in the clearance of lipoprotein remnants.”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Interpretationreasoning
The prevention of apoE4[R142C]-induced dyslipidemia by deletion of the 203-299 residues suggests that, in the full-length protein, the R142C substitution may have altered the conformation of apoE bound to VLDL/IDL/LDL in ways that prevent triglyceride hydrolysis, cholesterol esterification, and receptor-mediated clearance in vivo.
“The prevention of apoE4[R142C]-induced dyslipidemia by deletion of the 203-299 residues suggests that, in the full-length protein, the R142C substitution may have altered the conformation of apoE bound to VLDL/IDL/LDL in ways that prevent triglyceride hydrolysis, cholesterol esterifi cation, and receptormediated clearance in vivo.”
Quote in the paperSubstantial claim - Interpretationreasoning
The endogenous lipoprotein lipase was insufficient to hydrolyze the triglycerides of VLDL.
“indicated that the endogenous lipoprotein lipase was insuffi cient to hydrolyze the triglycerides of VLDL.”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
- Interpretationown data
The amino terminal portion of full-length apoE4[R142C] bound to lipoprotein particles assumes a configuration that masks its receptor-binding domain.
“This fi nding suggests that the amino terminal portion of the full-length apoE4[R142C] bound to lipoprotein particles assumes a confi guration that masks its receptor-binding domain.”
Quote in the paperSubstantial claim
- May combine two claims. 27
- Classified as probably not a substantial claim. 9
- The quote only partly states this claim. 2
May combine two claims.
Premisecitation§ Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4Mutations in apoE that diminish binding of apoE-containing lipoproteins to the LDL receptor are associated with high plasma cholesterol levels and cause premature atherosclerosis in humans and experimental animals.
“In vivo and in vitro studies have shown that mutations in apoE that diminish binding of apoE-containing lipoproteins to the LDL receptor are associated with high plasma cholesterol levels and cause premature atherosclerosis in humans and experimental animals ( 1-3, 7, 8 ).”
Quote in the paperSubstantial claim2 of 5 sources checked- cites [1] Plump, 1992, Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells, Cell. source
- cites [2] Schaefer, 1986, Familial apolipoprotein E deficiency, J. Clin. Invest. source
The Discussion (page unavailable) reports elevated cholesterol and premature cardiovascular events in members of the human apoE-deficient kindred, while noting that other risk factors may have contributed and that the events were not strikingly premature. The paper attributes the defect to markedly decreased apoE production, not a demonstrated mutation that diminishes LDL-receptor binding; it provides no experimental-animal finding for this claim. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [3] Reddick, 1994, Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression, Arterioscler. Thromb. source
The Abstract (p. 141) reports elevated plasma cholesterol and developing atherosclerotic lesions in apoE-deficient mice. The paper does not establish that apoE mutations diminish lipoprotein binding to the LDL receptor, or that such mutations cause premature atherosclerosis in humans. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [7] Mahley, 2001, Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism
Not checked in the free run.
- cites [8] Rall, 1992, The role of apolipoprotein E genetic variants in lipoprotein disorders, J. Intern. Med. source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4ApoE is involved in the biogenesis of distinct apoE-containing HDL species with the participation of ABCA1 and LCAT.
“Most recently we have shown that apoE is involved in the biogenesis of distinct apoE-containing HDL species with the participation of the ABCA1 lipid transporter and lecithin cholesterol acyltransferase (LCAT) ( 9 ).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [9] Kypreos, 2007, Pathway of biogenesis of apolipoprotein E-containing HDL in vivo with the participation of ABCA1 and LCAT, Biochem. J. source
May combine two claims.
FindingcitationGene transfer of either 2 or 3.5 × 10^9 pfu of adenovirus expressing WT apoE4-202 corrected the plasma cholesterol profile of apoE-/- mice and did not induce hypertriglyceridemia.
“Consistent with previous fi ndings ( 16 ), gene transfer of either 2 or 3.5 × 10 9 pfu of adenovirus expressing the WT apoE4-202 also corrected the plasma cholesterol profi le of apoE Ϫ / Ϫ mice and did not induce hypertriglyceridemia ( Fig. 7A, B ).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [16] Kypreos, 2001, Domains of apolipoprotein E contributing to triglyceride and cholesterol homeostasis in vivo. Carboxyl-terminal region 203–299 promotes hepatic very low density lipoprotein-triglyceride secretion, J. Biol. Chem. source
The Results (p. 4) report that 2 × 10^9 pfu of adenovirus expressing truncated apoE4-202 normalized cholesterol levels in apoE-deficient mice without causing hypertriglyceridemia. The paper reports a second dose of 10^10 pfu, not 3.5 × 10^9 pfu, so it does not establish the claim for that exact dose. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims.
InterpretationcitationThe increased levels of plasma LPL following gene transfer may promote lipoprotein clearance both by increasing the rate of lipolysis and exposing the receptor-binding domain of apoE, as well as by direct receptor-mediated clearance mechanisms involving LPL.
“The increased levels of plasma LPL following gene transfer may promote lipoprotein clearance both by increasing the rate of lipolysis and exposing the receptor-binding domain of apoE, as well as by direct receptor-mediated clearance mechanisms involving LPL ( 38,39 ).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [38] Salinelli, 1996, Structure-function relationship of lipoprotein lipase-mediated enhancement of very low density lipoprotein binding and catabolism by the low density lipoprotein receptor. Functional importance of a properly folded surface loop covering the catalytic center, J. Biol. Chem. source
- cites [39] Medh, 1996, Lipoprotein lipase binds to low density lipoprotein receptors and induces receptor-mediated catabolism of very low density lipoproteins in vitro, J. Biol. Chem. source
- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims.
PremisecitationSome of the mouse lines produced a phenotype characterized by mild hypercholesterolemia, hypertriglyceridemia, and very high levels of plasma apoE.
“Some of the mouse lines produced a phenotype characterized by mild hypercholesterolemia, hypertriglyceridemia, and very high levels of plasma apoE ( 30 ).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [30] Fazio, 1993, Type III hyperlipoproteinemic phenotype in transgenic mice expressing dysfunctional apolipoprotein E, J. Clin. Invest. source
The Results report that an intermediate-expressing line had mildly elevated plasma lipids, while Table I shows elevated cholesterol and triglycerides in several lines. But the lines with very high plasma apoE had substantially, rather than mildly, elevated cholesterol; the claim combines features observed at different apoE expression levels. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataIn apoE-/- mice infected with 5 × 10^8 pfu of adenoviruses expressing wild-type apoE4, over 85% of cholesterol was found in HDL-sized particles and was mostly esterified.
“FPLC analysis of plasma from apoE Ϫ / Ϫ mice infected with 5 × 10 8 pfu of adenoviruses expressing wild-type apoE4 showed that over 85% of the cholesterol was found in HDL-sized particles and was mostly esterifi ed ( Fig. 1E ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims.
Findingown dataInfection of apoE-/- mice with a low dose (5 × 10^8 pfu) of adenovirus expressing apoE4[R142C] increased plasma cholesterol over a four-day period and induced severe hypertriglyceridemia.
“infection of apoE Ϫ / Ϫ mice with a low dose (5 × 10 8 pfu) of an adenovirus expressing apoE4[R142C] increased plasma cholesterol over a fourday period and induced severe hypertriglyceridemia ( Fig. 1A , B ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims. The quote only partly states this claim.
Findingown dataWhen mice were infected with 5 × 10^8 pfu of adenovirus expressing apoE4[R142C], there was a dramatic increase of apoE in the VLDL/IDL/LDL region as well as a shift of apoE toward the HDL2 region.
“However, when the mice were infected with 5 × 10 8 pfu of adenovirus expressing apoE4[R142C] in addition to the apoE fl oating in the HDL3 region, there was a dramatic increase of apoE in the VLDL/IDL/LDL region as well as a shift of apoE toward the HDL2 region ( Fig. 2B ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims.
Findingown dataLCAT treatment significantly decreased plasma triglyceride levels and increased plasma apoE levels on days 2-4 postinfection in mice expressing apoE4[R142C].
“However, the LCAT treatment signifi cantly decreased plasma triglyceride levels and increased plasma apoE levels on days 2-4 postinfection ( Fig. 3B, C ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims.
Findingown dataCholesterol levels were reduced to approximately 250 mg/dl on day 1 and did not change significantly on days 2-4 postinfection in mice expressing apoE4[R142C]-202.
“The cholesterol levels were reduced to ف 250 mg/dl on day 1 and did not change signifi cantly on days 2-4 postinfection”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims.
Findingown dataInfection of apoE-/- mice with a similar dose (5 × 10^8 pfu) of adenovirus expressing wild-type apoE4 cleared cholesterol, did not affect plasma triglycerides levels, and caused only a small increase in plasma apoE levels.
“In contrast, infection of apoE Ϫ / Ϫ mice with a similar dose (5 × 10 8 pfu) of adenovirus expressing wild-type apoE4 cleared cholesterol, did not affect plasma triglycerides levels, and caused only a small increase in plasma apoE levels ( Fig. 1A-C ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims.
Findingown dataInfection with 6 × 10^8 pfu of adenovirus expressing apoE3 cleared cholesterol, did not increase plasma triglyceride levels, and all apoE was distributed in the HDL region.
“In contrast infection with 6 × 10 8 pfu of the adenovirus expressing apoE3 cleared cholesterol and did not increase plasma triglyceride levels and all apoE was distributed in the HDL region (supplementary Fig. 1A-C ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims.
Findingown dataTriglyceride levels were in the range of 35-70 mg/dl and were not affected by treatment with the truncated WT or mutant apoE form.
“Triglyceride levels were in the range of 35-70 mg/dl and were not affected by the treatment with the truncated WT or mutant apoE form (data not shown).”
Quote in the paperNot a substantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims.
Findingown dataCoinfection of apoE-/- mice with a mixture of 3.0 × 10^8 each of adenovirus expressing apoE4[R142C] and WT apoE3 increased plasma cholesterol levels, induced severe hypertriglyceridemia, and caused accumulation of apoE in the VLDL/IDL/LDL/HDL region.
“Coinfection of E Ϫ / Ϫ mice with a mixture of 3.0 × 10 8 each of adenovirus expressing apoE4[R142C] and WT apoE3 increased plasma cholesterol levels induced severe hypertriglyceridemia and caused accumulation of apoE in the VLDL/IDL/LDL/HDL region (supplementary Fig. IA, B, D ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims.
Findingown dataCholesterol levels of apoE-/- mice were reduced to approximately 100 mg/dl on day 1 and did not change significantly on days 2-4 postinfection.
“The cholesterol levels of apoE Ϫ / Ϫ mice were reduced to approximately 100 mg/dl on day 1 and did not change signifi cantly on days 2-4 postinfection ( Fig. 7A, B ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims.
Findingown dataIn apoE-/- mice infected with 5 × 10^8 pfu of adenoviruses expressing apoE4[R142C], the majority of cholesterol (over 90%) was distributed in the VLDL/IDL region, a small amount of cholesterol was found in HDL, and it was unesterified.
“In contrast, when apoE Ϫ / Ϫ mice were infected with 5 × 10 8 pfu of adenoviruses expressing apoE4[R142C], the majority of cholesterol (over 90%) was distributed in the VLDL/ IDL region, a small amount of cholesterol was found in HDL, and it was unesterifi ed ( Fig. 1F ).”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims.
Findingnone givenLCAT treatment partially corrected the hypertriglyceridemia and generated spherical HDL particles, but it did not correct the hypercholesterolemia.
“The LCAT treatment partially corrected the hypertriglyceridemia and generated spherical HDL particles, but it did not correct the hypercholesterolemia.”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims.
Findingown dataExpression of the truncated apoE4[R142C]-202 form in apoE-/- mice resulted in increased levels of free cholesterol in VLDL and formation of a shoulder of cholesterol spanning the IDL/LDL/HDL2 region compared with the truncated wild-type form.
“Expression of the truncated apoE4[R142C]-202 form in apoE Ϫ / Ϫ mice resulted in increased levels of free cholesterol in the VLDL and formation of a shoulder of cholesterol spanning the IDL/LDL/ HDL2 region compared with the truncated wild-type form.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAt high levels of expression, both the mutant and WT truncated apoE-202 forms inhibited the esterification of cholesterol in all lipoprotein fractions and promoted formation of discoidal HDL.
“A common property of the mutant and WT truncated apoE-202 forms is that, at high levels of expression, they also inhibited the esterifi cation of the cholesterol in all lipoprotein fractions and promoted formation of discoidal HDL.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe observed phenotype is characterized by severe hypercholesterolemia and hypertriglyceridemia, reduced CE/TC ratio in different lipoprotein fractions, formation of discoidal apoE-containing HDL, very high plasma apoE levels, and accumulation of apoE in the VLDL/IDL/LDL region.
“The observed phenotype is characterized by severe hypercholesterolemia and hypertriglyceridemia, reduced CE/TC ratio in different lipoprotein fractions, formation of discoidal apoE-containing HDL, very high plasma apoE levels, and accumulation of apoE in the VLDL/IDL/LDL region.”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims.
Findingown dataWestern blotting of FPLC fractions showed the HDL2 peak and the IDL/LDL shoulder was enriched in apoE, whereas the majority of mouse apoA-I appeared to be in the HDL3 and lipid-free fractions.
“Western blotting of FPLC fractions showed the HDL2 peak and the IDL/LDL shoulder was enriched in apoE, whereas the majority of mouse apoA-I appeared to be in the HDL3 and lipid-free fractions ( Fig. 7E, F , lower portion).”
Quote in the paperNot a substantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
The quote only partly states this claim.
Findingown dataCo-expression of apoE4[R142C] with LPL or LCAT partially or transiently corrects the apoE4[R142C]-induced dyslipidemia in apoE-/- mice.
“These defects can be transiently corrected by co-expression of apoE4[R142C] with LPL or LCAT.”
- Also stated in: § Gene transfer studies of the apoE4[R142C] mutant in E · plain
“Co-expression of apoE4[R142C] with lecithin cholesterol acyltransferase (LCAT) or lipoprotein lipase (LPL) in apoE ؊ / ؊ mice partially corrected the apoE4[R142C]induced dyslipidemia.”
Quote in the paperSubstantial claim- Also stated in: § Gene transfer studies of the apoE4[R142C] mutant in E · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4The recessive form of type III HLP is encountered in subjects with the E2/2 phenotype, which results from substitution of Cys for Arg-158.
“The recessive form of type III HLP is encountered in subjects with the E2/2 phenotype which results from the substitution of Cys for Arg-158 ( 10 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Breslow, 1982, Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE phenotype E2/2, J. Lipid Res. source
Classified as probably not a substantial claim.
Premisecitation§ Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4Certain apoE phenotypes and genotypes are associated with recessive or dominant forms of type III hyperlipoproteinemia.
“Certain apoE phenotypes and genotypes are associated with recessive or dominant forms of type III hyperlipoproteinemia (HLP).”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4ApoE is essential for clearance of lipoprotein remnants from the circulation and for atheroprotection.
“clearance of lipoprotein remnants from the circulation and is essential for atheroprotection (1)(2)(3).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (1)(2)(3)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4The degree of penetrance of type III HLP varies depending on the mutation.
“The degree of penetrance of the disease varies depending on the mutation ( 7 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Mahley, 2001, Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism
Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation§ Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4Lipoprotein-bound apoE is the ligand for the LDL receptor as well as other receptors in vitro.
“Lipoprotein-bound apoE is the ligand for the LDL receptor as well as other receptors in vitro (4)(5)(6).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (4)(5)(6)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4The E2/2 mutation combined with other genetic or environmental factors affects catabolism of apoE-containing lipoproteins and results in accumulation in plasma of remnants of lipoprotein catabolism.
“This mutation combined with other genetic or environmental factors affects the catabolism of apoE-containing lipoproteins and results in the accumulation in plasma of remnants of lipopro tein catabolism ( 7,11 ).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [7] Mahley, 2001, Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism
Not checked in the free run.
- cites [11] Havel, 1973, Primary dysbetalipoproteinemia: predominance of a specific apoprotein species in triglyceride-rich lipoproteins, Proc. Natl. Acad. Sci. USA. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationX-ray crystallography of lipid-free apoE isoforms showed that apoE4 is more compact than apoE3 due to differences in domain interactions.
“The X-ray crystallography of lipid-free apoE isoforms showed that apoE4 is more compact than apoE3 due to differences in domain interactions (44)(45)(46).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites (44)(45)(46)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataApoE4[R142C] affects in vivo the activity of LCAT and LPL, the maturation of HDL, and the clearance of triglyceride-rich lipoproteins.
“The fi ndings establish that apoE4[R142C] causes accumulation of apoE in VLDL/IDL/LDL region and affects in vivo the activity of LCAT and LPL, the maturation of HDL, and the clearance of triglyceride-rich lipoproteins.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationApoE contains N-terminal and C-terminal domains that unfold independently.
“ApoE contains N-terminal and C-terminal domains that unfold independently ( 42,43 ).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
InterpretationreasoningThe accumulation of apoE in VLDL/LDL/IDL appears to alter the functions of LPL and LCAT, cause hypertriglyceridemia, prevent lipoprotein clearance, and inhibit the maturation of discoidal into spherical HDL particles.
“The accumulation of apoE in VLDL/LDL/IDL appears to alter the functions of LPL and LCAT, cause hypertriglyceridemia, prevent lipoprotein clearance, and inhibit the maturation of the discoidal into spherical HDL particles.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe accumulation of apoE in the VLDL/IDL/LDL region appears to create insufficiency for both LPL and LCAT activity that can be transiently corrected by coexpression of the mutant apoE and either LPL or LCAT.
“The accumulation of apoE in the VLDL/IDL/LDL region appears to create insuffi ciency for both LPL and LCAT activity that can be transiently corrected by coexpression of the mutant apoE and either LPL or LCAT.”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
May combine two claims.
Interpretationown dataThe phenotype generated by apoE4[R142C] is dominant and persists when the mutant and the WT apoE are co-expressed in apoE-/- mice.
“The phenotype generated by apoE4[R142C] is dominant and persists when the mutant and the WT apoE are co-expressed in apoE Ϫ / Ϫ mice.”
Quote in the paperSubstantial claim- Rests on an assumption: Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAccelerated catabolism of discoidal particles and reduction in LCAT activity has been observed in subjects with apoA-I mutations.
“Accelerated catabolism of discoidal particles and reduction in LCAT activity has been observed in subjects with apoA-I mutations ( 34,35 ).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [34] Koukos, 2007, LCAT can rescue the abnormal phenotype produced by the natural ApoA-I mutations (Leu141Arg)Pisa and (Leu159Arg)FIN, Biochemistry. source
- cites [35] Miettinen, 1997, Apolipoprotein A-IFin. Dominantly inherited hypoalphalipoproteinemia due to a single base substitution in the apolipoprotein A-I gene, Arterioscler. Thromb. Vasc. Biol. source
The paper relies on this without support.
Human subjects or experimental animals homozygous for the R142C mutation have not been studied previously.
“Human subjects or experimental animals homozygous for the R142C mutation have not been studied previously.”
The paper relies on this without support.
Adenovirus-mediated gene transfer in apoE-/- mice is a valid model for the human dominant form of type III HLP caused by apoE4[R142C].
“Here we studied the molecular etiology of the dominant dyslipidemia caused by the apoE4[R142C] mutation using adenovirus-mediated gene transfer in apoE Ϫ / Ϫ mice.”
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A simplified system for generating recombinant adenoviruses
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Update on the molecular biology of dyslipidemias
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The clinical and laboratory investigation of dysbetalipoproteinemia
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Familial dysbetalipoproteinemia: highly atherogenic and underdiagnosed disorder
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Self-citationGenetic lipid disorders, the APOE gene and Familial Dysbetalipoproteinemia
Heidemann, B. E. (2022) · doi:10.33540/1408
- Authors
- Vezeridis, A. M., Drosatos, K., & Zannis, V. I.
- Affiliations
- Boston University (US)
- Corresponding author
- Zannis, Vassilis I.
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 52
- Issue
- 1
- Pages
- 45-56
- ISSN
- 0022-2275 (ISSN-L)
- PMC
- PMC2999928
- OpenAlex
- W2168127497
- Semantic Scholar
- 590a97e61b78e10645bc252453df3ce29c09045b
- Cited by
- 11
- References
- 53
- Citations by year
- 2022: 2 · 2021: 1 · 2020: 1 · 2016: 1 · 2015: 1 · 2014: 3 · 2013: 1
- FWCI
- 0.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (HL007969)
- National Heart, Lung, and Blood Institute (HL 68216, HL-007969, R01HL068216, T32HL007969)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- type III hyperlipoproteinemia, APOE ε4, dominant mutations, ApoE-deficient mice, adenoviral gene transfer, lecithin:cholesterol acyltransferase, lipoprotein lipase, discoidal HDL, cholesterol esterification, dyslipidemia
- MeSH terms
- Animals, Cells, Cultured, Humans, Hyperlipoproteinemia Type III, Phosphatidylcholine-Sterol O-Acyltransferase, Mice, Transgenic, Microscopy, Electron, Mutation, Phenotype, Triglycerides, Mice, Apolipoprotein E4
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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 2026-11-01.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-01.
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