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Cited by 254Cholesterol and Lipid MetabolismLipid metabolism and disordersLipoproteins and Cardiovascular Health

Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2.

Open access
Sullivan, P M, Mezdour, H, Quarfordt, S H, Maeda, N·1998·Journal of Clinical Investigation
DOI 10.1172/jci2673PMC PMC509074
Open this paper in CoChat — free accountOpen PDF

Abstract

To study isoform-specific effects of apolipoprotein E (apoE) in vivo, we generated mice with a human APOE*2 allele in place of the mouse Apoe gene via targeted gene replacement in embryonic stem cells. Mice expressing human apoE2 (2/2) have virtually all the characteristics of type III hyperlipoproteinemia. Their plasma cholesterol and triglyceride levels are both twice to three times those in (normolipidemic) mice that are expressing human apoE3 (3/3) made in an identical manner. The 2/2 mice are markedly defective in clearing beta-migrating VLDL particles, and spontaneously develop atherosclerotic plaques, even on a regular diet. An atherogenic diet, high in fat and cholesterol, exacerbates development of atherosclerosis and xanthomas in the 2/2 mice. Thus, comparisons between the 2/2 and 3/3 mice unequivocally demonstrate that a single amino acid difference (Arg158 Cys) in the apoE protein is sufficient to cause type III HLP and spontaneous atherosclerosis in mice.

AI snapshot

Written from the paper’s full text.

TL;DR

Targeted replacement of the mouse Apoe gene with human APOE*2 produced mice with virtually all features of type III hyperlipoproteinemia and spontaneous atherosclerosis, whereas mice carrying human APOE*3 made identically were normolipidemic. The paper concludes that a single amino acid difference (Arg158→Cys) in apoE is sufficient to cause type III HLP and spontaneous atherosclerosis in mice.

Key findings

  • APOE*2 homozygous (2/2) mice had plasma total cholesterol and triglycerides two to three times higher than APOE*3 homozygous (3/3) mice on normal chow; e.g., females: TC 238 ± 48 vs. 75 ± 15 mg/dl and TG 184 ± 46 vs. 48 ± 13 mg/dl (P < 0.0001). HDL cholesterol did not differ, and 2/3 heterozygotes had normal lipid levels.
  • 2/2 mice showed β-VLDL accumulation: broad β-migration on agarose gels, VLDL cholesterol-to-triglyceride ratio 0.76 vs. 0.03 in 3/3 mice, and ~65% of total cholesterol in VLDL-IDL fractions vs. >85% in HDL for 3/3 mice. Plasma apoE2 was 16-fold higher than apoE3 in 3/3 mice.
  • Clearance of radiolabeled apoE-deficient remnant particles was severely delayed in 2/2 mice: fractional catabolic rate 0.007/min vs. 0.02/min in 3/3 mice, with ~50% of label remaining at 2 h in 2/2 and apoE−/− mice.
  • 2/2 mice spontaneously developed atherosclerosis on regular chow: all seven 10-month-old females evaluated had plaques near the aortic root, average size 9.4 × 10^4 (as reported; text labels area units m²), vs. smaller plaques in 4 of 11 3/3 females, average 1 × 10^3. An atherogenic diet enhanced plaque size in 2/2 females to 5.3 × 10^5, eight times larger than 3/3 females (6.4 × 10^4), and caused xanthomas.

Methods

  • Gene replacement in mouse embryonic stem cells replaced the mouse Apoe gene with human APOE*2, using the same strategy previously used for APOE*3; mice were 129/C57BL/6 F2 hybrids, with 2/3 heterozygotes from F3 matings.
  • Mice were fed regular chow, an atherogenic diet (15.8% fat, 1.25% cholesterol, 0.5% sodium cholate), or a western-style diet (21% fat, 0.2% cholesterol). Plasma lipids, lipoproteins, apoE, and apoB were analyzed by enzymatic assays, agarose gel electrophoresis, FPLC, SDS-PAGE, and ELISA.
  • Remnant clearance was measured after injection of 14C-labeled β-VLDL from apoE−/− mice into 2/2, 3/3, and apoE−/− mice; atherosclerosis was assessed histologically in proximal aorta/aortic sinus sections. Statistical comparisons used two-tailed unpaired Student t tests or Mann-Whitney U tests.

Limitations

  • The paper has no explicit limitations section. It states that one of four 2/2 mice did not respond to clofibrate and the reason is unknown, possibly related to its F2 genetic background.
  • The authors state that mechanisms for different triglyceride and HDL responses to the western vs. atherogenic diets are unknown, though they attribute the differences most likely to diets rather than sex.
  • Evident from the text: the model may overstate human relevance because mice synthesize ~70% of liver-derived VLDL as apoB48 particles and depend more on apoE for VLDL remnant clearance than humans, so the apoE2 vs. apoE3 difference has a larger impact in mice than in most humans.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1172/jci2673

Cites

31 of 31 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 27 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Plasma cholesterol and triglyceride levels in 2/2 mice are both two to three times those in 3/3 mice.

    “Their plasma cholesterol and triglyceride levels are both twice to three times those in (normolipidemic) mice that are expressing human apoE3 (3/3) made in an identical manner.”
    • Also stated in: § Results · plain
      “plasma TC and TG levels in the 2/2 mice are two to three times higher than those in the 3/3 mice, which are themselves normolipidemic (Table I, P Ͻ 0.0001).”
    Quote in the paperSubstantial claim
  • Findingown data

    An atherogenic diet high in fat and cholesterol exacerbates development of atherosclerosis and xanthomas in 2/2 mice.

    “An atherogenic diet, high in fat and cholesterol, exacerbates development of atherosclerosis and xanthomas in the 2/2 mice.”
    • Also stated in: § Delayed clearance of VLDL and spontaneous atherosclerosis. · plain
      “Thus, a diet high in fat and cholesterol exacerbates the hyperlipidemia as well as development of atherosclerosis in the 2/2 animals.”
    Quote in the paperNot a substantial claim
  • Findingown data

    2/2 mice are markedly defective in clearing beta-migrating VLDL particles.

    “The 2/2 mice are markedly defective in clearing ␤ -migrating VLDL particles”
    • Also stated in: § Discussion · boosted
      “These results show that the 2/2 mice have a severe defect in clearing larger lipoproteins”
    Quote in the paperSubstantial claim
  • Findingown data

    Lesions in 3/3 mice consisted solely of foam cells.

    “In contrast, the lesions in the 3/3 mice consisted solely of foam cells (Fig. 3 C).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In the three responding 2/2 mice, mean plasma TG levels decreased from 188 mg/dl to 61 mg/dl (P<0.001).

    “In the three animals that responded, mean plasma TG levels decreased from elevated (188 mg/dl) to normal levels (61 mg/dl, P Ͻ 0.001).”
    Quote in the paperNot a substantial claim
  • The quote only partly states this claim. 3
  • May combine two claims. 27
  • Classified as probably not a substantial claim. 10

  • The quote only partly states this claim.

    Findingown data

    2/2 mice spontaneously develop atherosclerotic plaques even on a regular diet.

    “and spontaneously develop atherosclerotic plaques, even on a regular diet.”
    • Also stated in: § Delayed clearance of VLDL and spontaneous atherosclerosis. · plain
      “we found atherosclerotic plaques in the proximal aorta of 10-mo-old female 2/2 mice maintained on regular chow.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In 2/2 mice, >=65% of total cholesterol is in lipoproteins eluting in VLDL-IDL range (fractions 15-23); in 3/3 mice, >85% of cholesterol is in HDL range (fractions 27-31).

    “Accumulation of ␤ -VLDL in 2/2 plasma is further illustrated by fast protein liquid chromatography (FPLC), which shows that ‫ف‬ 65% of the total cholesterol is in lipoproteins that elute in the VLDL-intermediate density lipoprotein (IDL) range (fractions 15-23, Fig. 1 C ); in contrast, Ͼ 85% of the cholesterol in the 3/3 mice is in the HDL range (fractions 27-31).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Feeding the atherogenic diet for 3 mo enhanced plaque development in female 2/2 mice (mean size 5.3x10^5 um^2, n=9); plaques were eight times larger than those in 3/3 female mice (6.4x10^4 um^2, n=6) on the same diet.

    “Feeding the atherogenic diet for 3 mo enhanced plaque development in the female 2/2 mice (mean size, 5.3 ϫ 10 5 m 2 , n ϭ 9); and the plaques were eight times larger than those found in the 3/3 female mice (6.4 ϫ 10 4 m 2 , n ϭ 6) on the same diet.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Animals of both sexes are equally affected, and plasma lipid levels are elevated at 2 mo of age and remain stable for over 1 yr.

    “Animals of both sexes are equally affected, and plasma lipid levels are elevated at 2 mo of age and remain stable for over 1 yr.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Livers of 2/2 mice on the atherogenic diet appeared relatively normal on gross examination, while wild-type livers were enlarged and pale.

    “The livers of 2/2 mice on the atherogenic diet, however, appeared relatively normal on gross examination, while the wild-type livers were enlarged and pale.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All seven 2/2 females evaluated had plaques near the aortic root, with cross-sectional area ranging from 2x10^4 to 2x10^5 um^2 (average 9.4x10^4 um^2).

    “All seven 2/2 females evaluated had plaques near the aortic root, with a cross-sectional area ranging from 2 ϫ 10 4 to 2 ϫ 10 5 m 2 (average size, 9.4 ϫ 10 4 m 2 ).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both whole plasma and the d<1.006 g/ml density fraction of plasma from 2/2 mice show broad beta-migration pattern; 3/3 plasma shows virtually no lipid staining at beta-position.

    “Both whole plasma and the d Ͻ 1.006 g/ml density fraction of plasma from 2/2 mice show this broad ␤ -migration pattern (Fig. 1 B ); in contrast, 3/3 plasma shows virtually no lipid staining at the ␤ -position.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    On an atherogenic diet (15.8% fat, 1.25% cholesterol, 0.5% sodium cholate), female 2/2 mice had a fivefold increase in plasma TC (P<0.001), while TG and HDL cholesterol levels were significantly reduced (P<0.001).

    “On an atherogenic diet that contains 15.8% fat, 1.25% cholesterol, and 0.5% sodium cholate, female 2/2 mice responded with a fivefold increase in plasma TC (P Ͻ 0.001), while their TG and HDL cholesterol levels were significantly reduced (P Ͻ 0.001, Table I).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The amount of apoB100 in the LDL fraction of 2/2 mice is similar to that in 3/3 mice.

    “The amount of apoB100 in the LDL fraction of 2/2 mice was similar to that in the 3/3 mice (data not shown).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Plaques in 2/2 mice were composed mainly of foam cells and some fibrous caps.

    “Fig. 3 A shows a representative section with plaques composed mainly of foam cells and some fibrous caps.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    ApoB48 is increased equally in both VLDL and IDL-LDL fractions, while the increase in apoB100 is mainly in the VLDL fraction.

    “ApoB48 was increased equally in both VLDL and IDL-LDL fractions, while the increase in apoB100 was mainly in the VLDL fraction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The majority of TG in both 2/2 and 3/3 mice is in the VLDL fraction, although TG levels in 2/2 are much higher.

    “The majority of TG in both groups of mice is in the VLDL fraction, although the TG levels in the 2/2 mice are much higher than in the 3/3 mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Very much smaller plaques (average 1x10^3 um^2), typically accumulation of several foam cells, were found in only 4 of 11 female 3/3 mice aged 10-12 mo.

    “In contrast, very much smaller plaques (average size, 1 ϫ 10 3 m 2 ), typically an accumulation of several foam cells, were found in only 4 of 11 female 3/3 mice aged 10-12”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Lesions in 2/2 mice consisted chiefly of foam cells, and many also had fibrous caps, cholesterol clefts, and necrotic cores.

    “Although the lesions in the 2/2 mice consisted chiefly of foam cells, many also had fibrous caps, cholesterol clefts, and necrotic cores (Fig. 3 B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In wild-type livers, hepatocytes were enlarged with microvesicular lipid deposits, and numbers of anucleate and binucleate hepatocytes were increased.

    “In marked contrast, the hepatocytes in the wild-type livers were enlarged with microvesicular lipid deposits, and the numbers of anucleate and binucleate hepatocytes were increased (Fig. 3 F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ApoB100 and apoB48 amounts in 2/2 plasma are increased two- and eightfold, respectively, compared with 3/3 mice.

    “SDS-PAGE also revealed that both the ApoB100 and apoB48 amounts in 2/2 plasma were increased two-and eightfold, respectively, compared with the 3/3 mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    ApoE2 is associated with lipoproteins in the VLDL-IDL range and appears as two distinct peaks (fractions 15 and 20) by FPLC.

    “ApoE2 was associated with lipoproteins in the VLDL-IDL range, and appeared as two distinct peaks (fractions 15 and 20) by FPLC analysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After clofibrate treatment, FPLC showed a marked decrease in cholesterol and TG in the larger lipoproteins (VLDL-IDL range), while HDL cholesterol was increased.

    “FPLC analysis (Fig. 1 C ) showed a marked decrease in cholesterol and TG in the larger lipoproteins (VLDL-IDL range), while HDL cholesterol was increased.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When male 2/2 mice were placed on a western-style diet (21% fat, 0.2% cholesterol), their plasma TC levels tripled (P<0.001), with a slight but not statistically significant increase in TG and no change in HDL cholesterol.

    “When male 2/2 mice were placed on a western-style diet containing 21% fat and 0.2% cholesterol, their plasma TC levels tripled (P Ͻ 0.001), accompanied by a slight but not statistically significant increase in TG, and no change in HDL cholesterol (Table I).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Type III HLP is characterized by accumulation of chylomicron and VLDL remnants (beta-VLDL), resulting in elevated plasma TC and TG.

    “Type III hyperlipoproteinemia (HLP) 1 is characterized by accumulation of chylomicron and VLDL remnants, collectively termed ␤ -VLDL, which results in elevated plasma levels of total cholesterol (TC) and triglycerides (TG).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Mice depend more on apoE for VLDL remnant clearance than do humans, in whom all VLDL particles from liver contain apoB100 and can be cleared via LDL receptor independently of apoE.

    “Mice consequently depend more on apoE for VLDL remnant clearance than do humans, in whom all the VLDL particles from the liver contain apoB100 and can be cleared via the LDL receptor independently of apoE.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    A diet high in fat and cholesterol exacerbates the hyperlipidemia as well as development of atherosclerosis in 2/2 animals.

    “Thus, a diet high in fat and cholesterol exacerbates the hyperlipidemia as well as development of atherosclerosis in the 2/2 animals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The changes and differences between 2/2 and 3/3 mice suggest that apoE2 is an ineffective ligand for removing lipoproteins via hepatocellular lipoprotein receptors, thereby protecting hepatocytes from fatty changes while accelerating lipoprotein uptake by a default pathway likely involving macrophages and Kupffer cells.

    “These changes and their differences between the 2/2 and the 3/3 mice suggest that the apoE2 is an ineffective ligand for removing lipoproteins via hepatocellular lipoprotein receptors, thereby protecting hepatocytes from fatty changes while accelerating lipoprotein uptake by a default pathway that likely involves macrophages and Kupffer cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Differences between apoE2 and apoE3 isoforms have a much larger impact in mice than in most humans, possibly because mice synthesize ~70% of liver-derived VLDL as apoB48 particles.

    “The differences between the apoE2 and apoE3 isoforms have a much larger impact in mice than in most humans, possibly because mice synthesize ‫ف‬ 70% of their liver-derived VLDL as apoB48 particles (23,24).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    Diets high in fat and cholesterol exacerbate hyperlipoproteinemia in 2/2 animals, in agreement with inverse observation that changing to low-fat, low-cholesterol diet alleviates hyperlipidemia in most human type III HLP patients.

    “Diets high in fat and cholesterol exacerbate the hyperlipoproteinemia found in the 2/2 animals, in agreement with the inverse observation that changing to a low-fat, lowcholesterol diet alleviates the hyperlipidemia in most human type III HLP patients (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1]

      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

    The majority of apoE2 homozygotes have below average plasma cholesterol levels, but 5-10% of homozygotes develop type III HLP.

    “The majority of apoE2 homozygotes have below average plasma cholesterol levels, but 5-10% of homozygotes develop type III HLP.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisecitation

    Additional genetic, hormonal, or environmental factors are required to precipitate type III HLP in humans.

    “Thus, additional genetic, hormonal, or environmental factors are required to precipitate the disease (3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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). May combine two claims.

    Premisecitation

    Transgenic mice expressing low levels of human apoE2 are hypolipidemic, while those expressing high levels are hyperlipidemic.

    “For example, transgenic mice expressing low levels of human apoE2 are hypolipidemic, while those expressing high levels are hyperlipidemic (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Previous transgenic animals expressing apoE variants have some characteristics of type III HLP, but rigorous comparisons to apoE3 transgenic mice are not possible because transgenes were inserted in different copy numbers and chromosomal locations.

    “These animals have some of the characteristics of type III HLP, but rigorous comparisons to other transgenic mice expressing the common human apoE3 isoform are not possible because the transgenes were inserted into the genome in different copy numbers and in different chromosomal locations.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [5]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [6]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisecitation

    A VLDL cholesterol-to-triglyceride ratio >0.3 is diagnostic for type III HLP in humans.

    “(a ratio Ͼ 0.3 is diagnostic for type III HLP in humans [15]).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15]

      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

    Another distinguishing characteristic of patients with type III HLP is the presence of planar and dermal xanthomas.

    “Another distinguishing characteristic of patients with type III HLP is the presence of planar and dermal xanthomas (20,21).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [21]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • The quote only partly states this claim.

    Interpretationcitation

    The alterations in plasma lipoprotein profiles after clofibrate treatment in 2/2 mice are very similar to what has been observed in human patients treated with fibrates.

    “These alterations in plasma lipoprotein profiles after clofibrate treatment are again very similar to what has been observed in human patients treated with fibrates (19).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisenone given

    Presence of endogenous mouse apoE protein in some transgenic models complicates interpretation of phenotype.

    “Additionally, the presence of endogenous mouse apoE protein in some cases complicates the interpretation of the phenotype.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Mice with human APOE*3 allele in place of mouse Apoe express human apoE3 transcripts in a tissue-specific and physiological manner.

    “We have previously reported the use of a gene replacement strategy to generate mice with a human APOE*3 allele in place of the mouse Apoe gene, and have demonstrated that these mice express human apoE3 transcripts in a tissue-specific and physiological manner (10).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    It is reasonable to expect that human apoE proteins would not be as good ligands to mouse receptor(s) as they are to human receptor(s), and further reduction of this interaction after Arg158Cys substitution in apoE2 is the likely cause of hyperlipidemia in 2/2 mice even on regular chow.

    “It is reasonable to expect that human apoE proteins would not be as good ligands to mouse receptor(s) as they are to human receptor(s), and further reduction of this interaction after the Arg-158→Cys substitution in the apoE2 protein is the likely cause of the hyperlipidemia seen in the 2/2 mice, even on the regular chow.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Reduced plasma lipoprotein clearance due to hormonal, dietary, and genetic changes that lower LDL receptor expression is thought to be a factor that triggers type III HLP phenotype in human patients.

    “Reduced plasma lipoprotein clearance due to hormonal, dietary, and genetic changes that lower LDL receptor expression is thought to be a factor that triggers the type III HLP phenotype in human patients (1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    3/3 mice are more susceptible to diet-induced hyperlipidemia than wild-type mice, suggesting human apoE3 is still not as good a ligand to mouse receptor(s) as mouse apoE protein.

    “Nevertheless, the 3/3 mice are more susceptible to diet-induced hyperlipidemia than are wild-type mice (10), suggesting that human apoE3 is still not as good of a ligand to mouse receptor(s) as mouse apoE protein.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

37 of 37

  • The paper relies on this without support.

    The primary molecular cause of type III HLP is a dysfunctional form of apolipoprotein E.

    “The primary molecular cause of the disease is the presence of a dysfunctional form of apolipoprotein (apo) E, a critical ligand needed for plasma lipoprotein clearance.”

  • The paper relies on this without support.

    The majority of type III HLP individuals are homozygous for the apoE2 isoform.

    “The majority of type III HLP individuals are homozygous for the apoE2 isoform, although in rare instances dominant apoE mutations are associated with the disease.”

  • The paper relies on this without support.

    ApoE2 differs from apoE3 by a single amino acid substitution, cysteine at position 158 in place of arginine.

    “ApoE2 differs from the most common isoform, apoE3, by only a single amino acid substitution, cysteine at position 158 in place of arginine.”

  • The paper relies on this without support.

    Type III HLP is characterized by accumulation of chylomicron and VLDL remnants (beta-VLDL), resulting in elevated plasma TC and TG.

    “Type III hyperlipoproteinemia (HLP) 1 is characterized by accumulation of chylomicron and VLDL remnants, collectively termed ␤ -VLDL, which results in elevated plasma levels of total cholesterol (TC) and triglycerides (TG).”
4 of 4

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Related

Authors
Sullivan, P. M., Mezdour, H., Quarfordt, S. H., & Maeda, N.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • Duke University (US)
ORCID
Sullivan, P M
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
1998-07-01
Volume
102
Issue
1
Pages
130-135
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci2673
PMC
PMC509074
OpenAlex
W2009182898
Semantic Scholar
5c70c14be49e1fca602aaf2a63c7aa5e2341ef41
Cited by
254
References
33
Citations by year
2026: 3 · 2025: 8 · 2024: 9 · 2023: 17 · 2022: 16 · 2021: 8 · 2020: 11 · 2019: 6 · 2018: 3 · 2017: 6 · 2016: 4 · 2015: 8 · 2014: 15 · 2013: 11 · 2012: 14
FWCI
6.64
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (HL 42630)
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
type III hyperlipoproteinemia, apolipoprotein E isoforms, spontaneous atherosclerosis, xanthoma, VLDL clearance, serum cholesterol, plasma triglycerides, atherogenic diet
MeSH terms
Animals, Apolipoproteins E, Arteriosclerosis, Cholesterol, Clofibrate, Dietary Fats, Female, Humans, Hyperlipoproteinemia Type III, Lipoproteins, VLDL, Male, Triglycerides, Gene Targeting, Mice

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