Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma.
Open accessAbstract
Apolipoprotein (apo) E Leiden is a rare variant of human apoE characterized by defective receptor binding and associated with dominant transmission of type III hyperlipoproteinemia. In heterozygotes, apoE Leiden is present in higher concentrations in both total plasma and very low density lipoproteins (VLDL) than the other apoE allele product. In the present study we analyzed cell expression and plasma lipoprotein association of apoE Leiden to determine whether the unequal concentration of the two apoE allele products could be explained by differences in secretion rate from the hepatocyte or by preferential association with VLDL. We transfected the rat hepatoma cell line McA-RH7777 with apoE Leiden or normal human apoE3, and studied their secretion and media distribution. In pulse-chase experiments, the secretion of apoE Leiden was comparable to that of both human apoE3 and rat endogenous apoE, approaching 100% in 90 min. In similar transfection experiments, secreted apoE Leiden was significantly less glycosylated than normal apoE3 (21.7% vs. 36.6%, P < 0.005, n = 4), a finding also noted for apoE Leiden in human plasma. In in vitro incubation experiments, apoE Leiden showed a markedly higher preference for VLDL of normolipidemic human plasma when compared to both apoE3 (2.6-fold, P < 0.001) and apoE4 (1.6-fold, P < 0.001). These results suggest that the accumulation of apoE Leiden in VLDL derives from a high affinity of the mutant protein for the VLDL. This enrichment in defective apoE probably exacerbates impairment of VLDL removal from the circulation, thus contributing to the dominant transmission of type III hyperlipoproteinemia.
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Written from the paper’s full text.
TL;DR
ApoE Leiden is not hypersecreted by hepatoma cells; instead, it preferentially associates with VLDL in vitro, which may explain its accumulation in VLDL and dominant type III hyperlipoproteinemia. The mutant is also underglycosylated compared with normal apoE3.
Key findings
- Secretion of apoE Leiden was comparable to normal apoE3 and rat endogenous apoE, approaching 100% at 90 min in pulse-chase experiments, so its VLDL predominance is not due to hypersecretion.
- Secreted apoE Leiden was significantly less glycosylated than normal apoE3 (21.7 ± 3.8% vs. 36.6 ± 4.5%, P < 0.005, n = 4); the Cys112 form of apoE Leiden had normal glycosylation (40.5 ± 4.0%, n = 4).
- In vitro incubation with normolipidemic human plasma showed apoE Leiden had higher VLDL preference than apoE3 (2.6-fold, P < 0.001) and apoE4 (1.6-fold, P < 0.001). VLDL distribution was 11.4 ± 1.2% for apoE3, 18.9 ± 2.8% for apoE4, 28.2 ± 2.6% for apoE Leiden Cys112, and 29.8 ± 1.8% for apoE Leiden Arg112.
- Transfected apoE Leiden did not displace endogenous rat apoE from VLDL; rat endogenous apoE in VLDL was 14.7%, 14.4%, and 13.8% in apoE3-transfected, apoE Leiden-transfected, and nontransfected cells, respectively.
Methods
- ApoE Leiden expression vectors with Arg112 or Cys112 were constructed and transfected into rat hepatoma McA-RH7777 cells; HeLa cells were also used for glycosylation studies. Secretion was assessed by pulse-chase labeling with [35S]methionine, immunoprecipitation, and SDS-PAGE.
- Iodinated apoE variants were incubated with human plasma, separated by Superose 6 chromatography, and fractions were analyzed for cholesterol, triglyceride, and radioactivity.
- Statistical comparisons used one-tail Student’s t test.
Limitations
- The paper states no formal limitations section; the authors note that the physiologic relevance of reduced apoE Leiden glycosylation is unknown and that the structural change increasing VLDL preference is unknown.
- Evident from the text: the lipoprotein association findings come from in vitro incubations with human plasma and transfected cell models, not from in vivo turnover studies in humans.
- Evident from the text: glycosylation comparisons used n = 4, and plasma apoE Leiden analysis used a single heterozygous subject, so broader generalizability is uncertain.
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Cites
Statistics
Claims the paper makes
17 of 49 cited sources checked · 12 supported · 0 flagged · accuracy not yet measured
- Premisecitation§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1
ApoE Leiden is characterized by defective receptor binding.
“In in vitro assays, apoE Leiden is defective in its affinity for the low density lipoprotein (LDL) receptor (6, 11, 14)”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [6] Havekes, 1986, Apolipoprotein E3-Leiden. A new variant of human apolipoprotein E associated with familial type III hyperlipoproteinemia, Hum. Genet. source
- cites [11] Havekes, 1984, Functionally inactive apolipoprotein E3 in a type III hyperlipoproteinaemic patient, Eur. J. Clin. Invest. source
- cites [14] Wardell, 1989, Apolipoprotein E3-Leiden contains a seven-ami no acid insertion that is a tandem repeat of residues 121 to 127, J. Biol. Chem. source
- Premiseown data§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1
In heterozygotes, apoE Leiden is present in higher concentrations in total plasma than the other apoE allele product.
“In heterozygotes, apoE Leiden is present in higher concentrations in both total plasma and very low density lipoproteins (VLDL) than the other apoE allele product.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [6] Havekes, 1986, Apolipoprotein E3-Leiden. A new variant of human apolipoprotein E associated with familial type III hyperlipoproteinemia, Hum. Genet. source
- cites [11] Havekes, 1984, Functionally inactive apolipoprotein E3 in a type III hyperlipoproteinaemic patient, Eur. J. Clin. Invest. source
- cites [12] de Knijff, 1991, Familial dysbetalipoproteinemia associated with apolipoprotein E3-Leiden in an extended multigeneration pedigree, J. Clin. Invest. source
- Premiseown data§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1
In heterozygotes, apoE Leiden is present in higher concentrations in VLDL than the other apoE allele product.
“In heterozygotes, apoE Leiden is present in higher concentrations in both total plasma and very low density lipoproteins (VLDL) than the other apoE allele product.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [6] Havekes, 1986, Apolipoprotein E3-Leiden. A new variant of human apolipoprotein E associated with familial type III hyperlipoproteinemia, Hum. Genet. source
- cites [11] Havekes, 1984, Functionally inactive apolipoprotein E3 in a type III hyperlipoproteinaemic patient, Eur. J. Clin. Invest. source
- cites [12] de Knijff, 1991, Familial dysbetalipoproteinemia associated with apolipoprotein E3-Leiden in an extended multigeneration pedigree, J. Clin. Invest. source
- Interpretationreasoning§ DISCUSSION · p. 5
There are probably other properties of apoE or additional factors that help determine whether the mode of inheritance of type III hlp will be dominant or recessive.
“Instead, it is probably that there are other properties of apoE or additional factors that help determine whether the mode of inheritance of type III hlp will be dominant or recessive (3, 12, 22).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [3] Mahley, 1990, Apolipoprotein E: genetic variants provide insights into its structure and function, Curr. Opin. Lipidol. source
- cites [12] de Knijff, 1991, Familial dysbetalipoproteinemia associated with apolipoprotein E3-Leiden in an extended multigeneration pedigree, J. Clin. Invest. source
- cites [22] 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
- Premisecitation§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1
In in vitro assays, apoE Leiden is defective in its affinity for the LDL receptor, having about 25% of normal apoE3 binding affinity.
“In in vitro assays, apoE Leiden is defective in its affinity for the low density lipoprotein (LDL) receptor (6, 11, 14), having about 25% of normal apoE3 binding affinity.”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [6] Havekes, 1986, Apolipoprotein E3-Leiden. A new variant of human apolipoprotein E associated with familial type III hyperlipoproteinemia, Hum. Genet. source
- cites [11] Havekes, 1984, Functionally inactive apolipoprotein E3 in a type III hyperlipoproteinaemic patient, Eur. J. Clin. Invest. source
- cites [14] Wardell, 1989, Apolipoprotein E3-Leiden contains a seven-ami no acid insertion that is a tandem repeat of residues 121 to 127, J. Biol. Chem. source
- Findingown data§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1
Secretion efficiency of apoE Leiden approaches 100% at 90 min in pulse-chase experiments.
“In pulse-chase experiments, the secretion of apoE Leiden was comparable to that of both human apoE3 and rat endogenous apoE, approaching 100% in 90 min.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS · p. 4
Transfected apoE did not modify secretion of endogenous rat apoE (about 0.6 μg/mg cell protein per h in both transfected and nontransfected cells).
“and did not modify secretion of endogenous rat apoE (about 0.6 μg/mg cell protein per h in both transfected cells and in the nontransfected line).”
Quote in the paperSubstantial claim - Findingown data§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1
Secretion of apoE Leiden by transfected rat hepatoma cells is comparable to that of human apoE3.
“In pulse-chase experiments, the secretion of apoE Leiden was comparable to that of both human apoE3 and rat endogenous apoE, approaching 100% in 90 min.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS · p. 4
Rat endogenous apoE is not displaced from VLDL by either apoE3 or apoE Leiden.
“and that rat endogenous apoE was not displaced from VLDL by either apoE3 or apoE Leiden”
Quote in the paperNot a substantial claim - Findingown data§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1
Underglycosylation of apoE Leiden is also observed in human plasma.
“a finding also noted for apoE Leiden in human plasma.”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS · p. 4
Rat endogenous apoE in VLDL was 14.7%, 14.4%, and 13.8% of total rat apoE in apoE3-transfected, apoE Leiden-transfected, and nontransfected cells, respectively.
“Rat endogenous apoE in VLDL was 14.7%, 14.4%, and 13.8% of total rat apoE in apoE3-transfected, apoE Leiden-transfected, and nontransfected cells, respectively.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS · p. 4
Secretion of transfected apoE is comparable in apoE3- and apoE Leiden-transfected McA-RH7777 cells (5.71 vs 5.35 μg/mg cell protein per h).
“Secretion of transfected apoE was comparable in the two cell linés (5.71 μg/mg cell protein per h for apoE3 versus 5.35 for apoE Leiden)”
Quote in the paperSubstantial claim - Findingown data§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1
Secretion of apoE Leiden by transfected rat hepatoma cells is comparable to that of rat endogenous apoE.
“In pulse-chase experiments, the secretion of apoE Leiden was comparable to that of both human apoE3 and rat endogenous apoE, approaching 100% in 90 min.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS · p. 3
The degree of glycosylation of apoE Leiden with cysteine at position 112 is normal (40.5 ± 4.0%, n = 4).
“However, the degree of glycosylation of the mutant with cysteine (instead of arginine) at position 112 (Fig. 2, lanes 2 and 5) was normal (40.5 ± 4.0%, n = 4).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS · p. 3
Underglycosylation of apoE Leiden also occurs in HeLa cells.
“This phenomenon occurred not only in the rat hepatoma cell line (Fig. 2, lanes 1 and 3) but also in Hela cells (Fig. 2, lanes 4 and 6), which do not make lipoproteins.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION · p. 4
The substitution of cysteine for arginine at position 112 does not affect the affinity of apoE Leiden for VLDL.
“when we tested the apoE Leiden containing cysteine-112, we found that its association with VLDL was not significantly different compared to apoE Leiden(Arg112).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS · p. 4
ApoE Leiden produced by transfected cells has the same distribution pattern among media lipoproteins as normal human apoE3.
“Results shown in Fig. 4 indicate that apoE Leiden produced by transfected cells had the same distribution pattern as normal human apoE3”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION · p. 4
The insertional mutation appears to negate the influence exerted by the polymorphism at site 112 on the lipoprotein association of apoE Leiden.
“Therefore, the insertional mutation appears to negate the influence exerted by the polymorphism at site 112 on the lipoprotein association of apoE Leiden.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION · p. 4
The preferential association of apoE Leiden with plasma VLDL contributes to β-VLDL accumulation.
“Instead, our results suggest that the preferential association of apoE Leiden with plasma VLDL is contributing to β-VLDL accumulation.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION · p. 5
ApoE Leiden does not associate with VLDL in the plasma of affected human subjects at the expense of the other allele product.
“Since we found that the transfected apoE Leiden does not disturb the distribution of endogenous apoE among lipoproteins (Fig. 4), it appears that apoE Leiden does not associate with VLDL in the plasma of affected human subjects at the expense of the other allele product.”
Quote in the paperSubstantial claim - Premisecitation§ DISCUSSION · p. 5
Type III hlp can be inherited in either a recessive or a dominant fashion.
“Type III hlp can be inherited in either a recessive or a dominant fashion (3).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Mahley, 1990, Apolipoprotein E: genetic variants provide insights into its structure and function, Curr. Opin. Lipidol. source
- Interpretationown data§ RESULTS · p. 4
The presence of the insertional mutation is responsible for directing apoE Leiden to VLDL.
“indicating that the presence of the insertional mutation is responsible for directing apoE Leiden to VLDL.”
Quote in the paperSubstantial claim - Premisecitation§ DISCUSSION · p. 4
The seven-amino acid insertion in apoE Leiden occurs in a loop that connects helix 3 to helix 4 in the 4-helical bundle of the amino-terminal domain of apoE.
“The sevenamino acid insertion in apoE Leiden occurs in a loop that connectshelix 3 to helix 4 in the 4-helical bundle of the amino-terminal domain of apoE(25).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Wilson, 1991, Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E., Science. source
- Interpretationown data§ DISCUSSION · p. 4
The predominance of apoE Leiden in affected subjects' VLDL is probably not due to overexpression of the mutant apoE.
“Our results show that the predominance of apoE Leiden in affected subjects' VLDL probably is not due to overexpression of the mutant apoE (Fig. 1).”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION · p. 5
The preferential association of a receptor-binding-defective apoE with VLDL may help to explain the mode of inheritance of type III hlp in apoE Leiden subjects.
“This preferential association of a receptor-binding-defective apoEwith the VLDL may help to explain the mode of inheritance of type III hlp in apoE Leiden subjects.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION · p. 4
The mutation directly determines an increased affinity of apoE Leiden for triglyceride-rich lipoproteins.
“Moreover, the mutation directly determines an increased affinity of apoE Leiden for triglyceride-rich lipoproteins.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION · p. 6
The accumulation of apoE Leiden in VLDL appears to be a postsecretory phenomenon.
“In conclusion, the accumulation of apoE Leiden in VLDL appears to be a postsecretory phenomenon.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION · p. 5
The reason for the difference in inheritance mode cannot be attributed solely to differences in receptor binding of apoE.
“The reason(s) for this difference is not known, but it cannot be attributed solely to differences in receptor binding of apoE.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION · p. 5
The interactions affecting the glycosylation of apoE Leiden appear complex, since both the insertion and the polymorphism at site 112 are involved.
“The interactions affecting the glycosylation of apoE Leiden appear to be complex, since both the insertion and the polymorphism at site 112 (where the presence of cysteine restores normal glycosylation) are involved.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ DISCUSSION · p. 5
It is unlikely that all apoE variants associated with dominant transmission of type III hlp will demonstrate the lipoprotein preference phenomenon.
“It is unlikely that all apoE variants associated with dominant transmission of type III hlp will demonstrate the lipoprotein preference phenomenon, since all others known to date do not have either insertions or Arg-112.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION · p. 6
The enrichment in defective apoE may help to explain the dominant transmission of type III hlp in subjects carrying the apoE Leiden mutation.
“and may help to explain the dominant transmission of type III hlp in subjects carrying the apoE Leiden mutation.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION · p. 5
The underglycosylation of apoE Leiden probably is due to a change in accessibility of the glycosylation site to the cell's glycosylation machinery.
“since the only glycosylation site in apoE is at threonine 194 (16), the underglycosylation of apoE Leiden probably is due to a change in accessibility of the glycosylation site to the cell's glycosylation machinery.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Wernette-Hammond, 1989, Glycosylation of human apolipoprotein E. The carbohydrate attachment site is threonine 194, J. Biol. Chem. source
- Interpretationown data§ DISCUSSION · p. 5
The reduced glycosylation of apoE Leiden does not appear to be related to the ability of the cell to synthesize lipoproteins.
“This observation does not appear to be related to the ability of the cell to synthesize lipoproteins, since it is evident in both McARH7777 and HeLa cells.”
Quote in the paperNot a substantial claim - Premisereasoning§ DISCUSSION · p. 5
ApoE2 is associated with a recessive mode of inheritance of type III hlp.
“Hence, apoE2(Cys112, Cys158) is associated with a recessive mode of inheritance of type III hlp.”
Quote in the paperSubstantial claim - Premisecitation§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1
Homozygosity for apoE2 is associated with recessive transmission of type III hlp.
“Homozygosity for the polymorphic form apoE2(Cys112, Cys158), the most common of these defective variants, is associated with recessive transmission of type III hlp (4).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] Utermann, 1975, Familial hyperlipoproteinemia type III: deficiency of a specific apolipoprotein (apoE-III) in the very-low-density lipoproteins, FEBS Lett. source
- Premisecitation§ RESULTS · p. 4
McA-RH7777 cells are known to synthesize VLDL.
“Because McA-RH7777 cells are known to synthesize VLDL (24)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Tanabe, 1989, Biogenesis of plasma lipoproteins in rat hepatoma McA-RH7777: importance of diffusion-mediated events during cell growth, In Vitro. source
- Classified as probably not a substantial claim. 12
- The quote only partly states this claim. 1
- May combine two claims. 11
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1ApoE Leiden is a rare variant of human apolipoprotein E.
“ApoE Leiden, one of the most thoroughly studied of the rare apoE variants (6, 11, 12)”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [6] Havekes, 1986, Apolipoprotein E3-Leiden. A new variant of human apolipoprotein E associated with familial type III hyperlipoproteinemia, Hum. Genet. source
- cites [11] Havekes, 1984, Functionally inactive apolipoprotein E3 in a type III hyperlipoproteinaemic patient, Eur. J. Clin. Invest. source
- cites [12] de Knijff, 1991, Familial dysbetalipoproteinemia associated with apolipoprotein E3-Leiden in an extended multigeneration pedigree, J. Clin. Invest. source
Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.
Premisecitation§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1ApoE Leiden is associated with dominant transmission of type III hyperlipoproteinemia.
“All subjects carrying the apoE Leiden mutation are heterozygotes, but all demonstrate type III hlp, although to varying degrees (12).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [12] de Knijff, 1991, Familial dysbetalipoproteinemia associated with apolipoprotein E3-Leiden in an extended multigeneration pedigree, J. Clin. Invest. source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSION · p. 5Glycosylation does not affect apoE binding to the LDL receptor.
“it does not affect apoE binding to the LDL receptor (27, 28)”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [27] Vogel, 1985, Human apolipoprotein E expression in Escherichia coli: structural and functional identity of the bacterially produced protein with plasma apolipoprotein E, Proc. Natl. Acad. Sci. USA. source
The Results and Discussion report essentially identical LDL-receptor binding for bacterially produced and authentic apoE in fibroblast assays. Our copy does not directly test glycosylation or state that it has no effect on binding, so the claim goes beyond the comparison reported. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [28] Rail, 1985, The carbohydrate moiety of human plasma apolipoprotein E., Circulation.
Not checked in the free run.
May combine two claims.
Premisecitation§ DISCUSSION · p. 5Both apoE Leiden and another apoE variant that shows preferential in vitro association with VLDL are found in much higher concentrations compared with normal apoE in affected subjects' VLDL, at a ratio of 4:1 or higher in the former and 3:1 in the latter.
“In contrast, both apoE Leiden and another apoE variant that shows a preferential in vitro association with VLDL (22) are found in much higher concentrations compared with normal apoE in affected subjects' VLDL, at a ratio of 4:1 or higher in the former instance (12) and 3:1 in the latter instance (22).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [12] de Knijff, 1991, Familial dysbetalipoproteinemia associated with apolipoprotein E3-Leiden in an extended multigeneration pedigree, J. Clin. Invest. source
The citation to this paper is attached to the apoE3-Leiden finding, not the other variant’s 3:1 ratio. The ‘Effect of the second APOE allele’ section says apoE3-Leiden makes up the majority of apoE in affected subjects’ VLDL, but the passages found do not establish the claimed ratio of 4:1 or higher. (LLM, conf=0.81)
Experimental — accuracy not yet measured - cites [22] 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
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1ApoE Leiden is characterized by a tandem repetition of amino acids 121-127 and has arginines at both polymorphic sites 112 and 158.
“ApoE Leiden, one of the most thoroughly studied of the rare apoE variants (6, 11, 12), is characterized by the presence of a tandem repetition of amino acids 121-127 and has arginines at both polymorphic sites 112 and 158 (13, 14).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [13] van den Maagdenberg, 1989, Apolipoprotein E*3-Leiden allele results from a partial gene duplication in exon 4, Biochem. Biophys. Res. Commun. source
- cites [14] Wardell, 1989, Apolipoprotein E3-Leiden contains a seven-ami no acid insertion that is a tandem repeat of residues 121 to 127, J. Biol. Chem. source
May combine two claims.
Premisecitation§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1All subjects carrying the apoE Leiden mutation are heterozygotes, but all demonstrate type III hlp, although to varying degrees.
“All subjects carrying the apoE Leiden mutation are heterozygotes, but all demonstrate type III hlp, although to varying degrees (12).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [12] de Knijff, 1991, Familial dysbetalipoproteinemia associated with apolipoprotein E3-Leiden in an extended multigeneration pedigree, J. Clin. Invest. source
May combine two claims.
Premisecitation§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1Subjects heterozygous for the apoE Leiden mutation show a predominance of the variant apoE over the wild-type protein in total plasma, but especially in the VLDL fraction (4:1 ratio or higher).
“Interestingly, subjects heterozygous for the apoE Leiden mutation show a predominance of the variant apoE over the wild-type protein in total plasma, but especially in the VLDL fraction (4:1 ratio or higher) (6, 11, 12)”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [6] Havekes, 1986, Apolipoprotein E3-Leiden. A new variant of human apolipoprotein E associated with familial type III hyperlipoproteinemia, Hum. Genet. source
- cites [11] Havekes, 1984, Functionally inactive apolipoprotein E3 in a type III hyperlipoproteinaemic patient, Eur. J. Clin. Invest. source
- cites [12] de Knijff, 1991, Familial dysbetalipoproteinemia associated with apolipoprotein E3-Leiden in an extended multigeneration pedigree, J. Clin. Invest. source
The Discussion (page unavailable) says apoE3-Leiden largely predominates over normal apoE in plasma. The ‘Effect of the second APOE allele’ section (page unavailable) says it makes up the majority of apoE in VLDL and IDL, but gives no 4:1 ratio; it also notes that the fraction-by-fraction pattern differs when the second allele is E4. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
Premisecitation§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1ApoE Leiden is considerably more active in receptor binding than apoE2, which exhibits less than 2% of normal apoE3 binding.
“ApoE Leiden is considerably more active in receptor binding than apoE2 (6, 14), which exhibits less than 2% of normal apoE3 binding.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [6] Havekes, 1986, Apolipoprotein E3-Leiden. A new variant of human apolipoprotein E associated with familial type III hyperlipoproteinemia, Hum. Genet. source
- cites [14] Wardell, 1989, Apolipoprotein E3-Leiden contains a seven-ami no acid insertion that is a tandem repeat of residues 121 to 127, J. Biol. Chem. source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1Certain other apoE variants are associated with a dominant mode of inheritance, i.e., heterozygosity is sufficient for expression of type III hlp.
“In contrast, certain other apoE variants are associated with a dominant mode of inheritance (5-10), i.e., heterozygosity for these apoE variants is sufficient for the expression of type III hlp.”
Quote in the paperNot a substantial claim4 of 6 sources checked- cites [5] Rail, 1989, Type III hyperlipoproteinemia associated with apolipoprotein E phenotype E3/3: structure and genetics of an apolipoprotein E3 variant, J. Clin. Invest. source
- cites [6] Havekes, 1986, Apolipoprotein E3-Leiden. A new variant of human apolipoprotein E associated with familial type III hyperlipoproteinemia, Hum. Genet. source
- cites [7] Wardell, 1987, Apolipoprotein E2-Christchurch (136 Arg → Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia, J. Clin. Invest. source
The Introduction reports that heterozygosity for apoE2 has been observed in people with type III hyperlipoproteinemia, supporting an association. It does not establish that heterozygosity is sufficient or that these variants have a dominant mode of inheritance. The Results describe a daughter who inherited apoE2-Christchurch but had no symptoms of type III hyperlipoproteinemia. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [8] Mann, 1989, Apolipoprotein E-1Harrisburg, a mutation in the receptor binding domain, that is dominant for dysbetalipoproteinemia results in defective ligand-receptor interactions, Clin. Res.
Not checked in the free run.
- cites [9] Rail, 1983, Identification of a new structural variant of human apolipoprotein E, E2(Lys146→Gln), in a type III hyperlipoproteinemic subject with the E3/2 phenotype, J. Clin. Invest. source
In the Apolipoprotein E2(Lys146-Gln) discussion (page unavailable), the paper reports type III hyperlipoproteinemia in an E3/2 heterozygote. But it suggests that a separate heritable abnormality may be required to trigger the disease in that subject, so it does not establish that heterozygosity for the variant is sufficient or that inheritance is dominant. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [10] Smit, 1990, Genetic heterogeneity in familial dysbetalipoproteinemia. The E2(lysl46→gln) variant results in a dominant mode of inheritance, J. Lipid Res. source
May combine two claims.
Findingown data§ DISCUSSION · p. 4About 28-30% of apoE Leiden associates with VLDL, compared to 11% of apoE3 and 19% of apoE4.
“About 28-30% of apoE Leiden associated with VLDL, compared to only 11% of apoE3 and 19% of apoE4 (Fig. 3, Table 1).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ DISCUSSION · p. 5Glycosylation does not influence apoE distribution among lipoproteins.
“and it does not influence apoE distribution amonglipoproteins (data not shown).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationreasoning§ DISCUSSION · p. 4The insertion apparently disrupts the relationship of site 112 with the lipid-binding carboxyl-terminal domain, while causing an unknown structural change that increases the preference of the protein for VLDL.
“The insertion apparently disrupts the relationship of site 112 (which lies in helix 3) with the lipid-binding carboxyl-terminal domain, while at the same time causing an as yet unknown structural change that increases the preference of the protein for VLDL.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Premisecitation§ DISCUSSION · p. 4The difference in lipoprotein distribution between apoE3 and apoE4 is due to the polymorphism at position 112, where arginine directs the apoprotein more to VLDL.
“The difference in lipoprotein distribution between apoE3 and apoE4 has been shown to be due to the polymorphism at position 112 (21), where the presence of an arginine directs the apoprotein more to the VLDL.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Weisgraber, 1990, Apolipoprotein E distribution among human plasma lipoproteins: role of the cysteine-arginine interchange at residue 112, J. Lipid Res. source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSION · p. 5Glycosylation is not necessary for proper intracellular processing and secretion of apoE.
“glycosylation is not necessary for proper intracellular processing and secretion of the protein (16)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Wernette-Hammond, 1989, Glycosylation of human apolipoprotein E. The carbohydrate attachment site is threonine 194, J. Biol. Chem. source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSION · p. 5The only glycosylation site in apoE is at threonine 194.
“since the only glycosylation site in apoE is at threonine 194 (16)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Wernette-Hammond, 1989, Glycosylation of human apolipoprotein E. The carbohydrate attachment site is threonine 194, J. Biol. Chem. source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1Several receptor-binding-defective variants of apoE are associated with impaired catabolism of remnant particles, leading to type III hlp.
“Several receptor-bindingdefective variants of apoE have been identified that are associated with impaired catabolism of remnant particles, leading to the development of type III hyperlipoproteinemia (type III hlp) (3).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] Mahley, 1990, Apolipoprotein E: genetic variants provide insights into its structure and function, Curr. Opin. Lipidol. source
May combine two claims.
Premisecitation§ DISCUSSION · p. 5In apoE3/2 subjects, apoE2 concentration is about 40% higher than apoE3 in VLDL, but these subjects do not develop type III hlp or demonstrate β-VLDL.
“While this occurs to a modest extent in apoE3/2 subjects (apoE2 concentration is found to be about 40% higher than apoE3 inVLDL), these subjects do not develop type III hlp or demonstrate β-VLDL (26).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Utermann, 1982, Apolipoprotein E (role in lipoprotein metabolism and pathophysiology of hyperlipoproteinemia type III), La Ricerca Clin. Lab. source
May combine two claims.
Interpretationreasoning§ DISCUSSION · p. 6The enrichment in defective apoE probably renders the VLDL less susceptible to receptor-mediated catabolism, exacerbating the accumulation of β-VLDL.
“The enrichment in defective apoE probably renders the VLDL less susceptible to receptor-mediated catabolism, exacerbating the accumulation of β-VLDL”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ DISCUSSION · p. 5The natural preference of apoE variants for VLDL helps to exaggerate the differential catabolism of normal and variant apoE, leading to accumulation of particles containing relatively more defective ligand and ultimately exacerbating β-VLDL formation and/or accumulation.
“We believe that in both these instances, the naturalpreference of the apoE variants for VLDL helps to exaggerate the differential catabolism of the normal and variant apoE, leading to accumulation of particles containing relatively more of the defective ligand and ultimately exacerbating β-VLDL formation and/or accumulation”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Preferential association of apolipoprotein E Leiden with very low density lipoproteins of of human plasma · p. 1ApoE is the ligand for VLDL and chylomicron remnant clearance by liver receptors.
“Apolipoprotein (apo) E, a polymorphic protein in humans, is the ligand for very low density lipoprotein (VLDL) and chylomicron remnant clearance by liver receptors (1).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Mahley, 1989, Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ RESULTS · p. 4The polymorphism at position 112 affects the affinity of apoE for lipoproteins, with apoE4 preferring VLDL to HDL relative to apoE3, which prefers HDL to VLDL.
“It has been demonstrated previously that the polymorphis at position 112 affects the affinity of apoE for lipoproteins, with apoE4 (arginine 112) preferring VLDL to HDL relative to apoE3, which prefers HDL to VLDL (21).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Weisgraber, 1990, Apolipoprotein E distribution among human plasma lipoproteins: role of the cysteine-arginine interchange at residue 112, J. Lipid Res. source
The paper relies on this without support.
The in vitro distribution of iodinated apoE among human plasma lipoproteins reflects the in vivo distribution of apoE among lipoproteins in human subjects.
“Incubation of the iodinated protein with humanplasma in vitro was done as reported previously (21).”
“we studied the affinity of apoE Leiden for lipoproteins in vitro.”
The paper relies on this without support.
The rat hepatoma cell line McA-RH7777 processes and secretes human apoE in a manner representative of human hepatocytes.
“We transfected the rat hepatoma cell line McA-RH7777 with apoE Leiden or normal human apoE3, and studied their secretion and media distribution.”
“Because McA-RH7777 cells are known to synthesize VLDL (24)”
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Self-citationFunctionally inactive apolipoprotein E<sub>3</sub> in a type III hyperlipoproteinaemic patient
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Flagged first, then by citations
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Self-citationDetermination of the lower threshold of apolipoprotein E resulting in remnant lipoprotein clearance
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Glycomic Analysis of High Density Lipoprotein Shows a Highly Sialylated Particle
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Association of human apolipoprotein E with lipoproteins secreted by transfected McA RH7777 cells
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Clinical Aspects of Gout and Associated Disease States
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Self-citationGounden, N. (1993) · ResearchSpace (University of KwaZulu-Natal)
- Authors
- Fazio, S., Horie, Y., Weisgraber, K., Havekes, L., & Rall, S.
- Affiliations
- Netherlands Organisation for Applied Scientific Research (NL)
- University of California, San Francisco (US)
- ORCID
- Fazio, S
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 1993-03
- Volume
- 34
- Issue
- 3
- Pages
- 447-453
- ISSN
- 0022-2275 (ISSN-L)
- OpenAlex
- W2106800224
- Cited by
- 23
- References
- 31
- Citations by year
- 2022: 1 · 2015: 1 · 2014: 1 · 2012: 1
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- TNO Repository (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Repository hosted by TU Delft Library (TU Delft) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL-41633, P01HL041633)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- apolipoprotein E, VLDL, type III hyperlipoproteinemia, lipoprotein binding, hepatocyte secretion, APOE3, APOE ε4, serum lipoproteins
- MeSH terms
- Animals, Apolipoproteins E, DNA, Glycosylation, Heterozygote, Humans, Hyperlipoproteinemia Type III, Lipoproteins, VLDL, Liver Neoplasms, Experimental, Transfection, Tumor Cells, Cultured, Rats, Apolipoprotein E3
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Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.
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