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Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apoe with human Apoe*2.
Open accessAbstract
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.
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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.
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Claims the paper makes
42 Own result · 20 Sources not found · 17 Own interpretation · 2 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Abstract
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- Also stated in: § Results · plain
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In the paper
“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.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Abstract
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- Also stated in: § Delayed clearance of VLDL and spontaneous atherosclerosis. · plain
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In the paper
“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”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Abstract
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In the paper
“In contrast, the lesions in the 3/3 mice consisted solely of foam cells (Fig. 3 C).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Delayed clearance of VLDL and spontaneous atherosclerosis.
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In the paper
“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).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Distribution of lipids and lipoproteins.
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In the paper
“Isoelectric focusing of whole plasma from mice homozygous for APOE*2 (2/2), heterozygous for APOE*2 and ApoE*3 (2/3), and homozygous for APOE*3 (3/3) shows that the mice are producing human apoE2 and apoE3 isoforms indistinguishable from those present in human plasma (Fig. 1 A ).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Results
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In the paper
“However, unlike humans in which apoE2 homozygosity is necessary but not sufficient to cause type III HLP, all the 2/2 mice, regardless of gender and age, develop hyperlipidemia, even on a low-fat and low-cholesterol diet.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Results
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“Lipid-laden macrophages were abundantly present in other tissues such as the fa-cial plane of skeletal muscle, submucosa of the esophagus, and the lymph nodes.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Delayed clearance of VLDL and spontaneous atherosclerosis.
plainn = 2- Asserted: passes — The authors put it forward as true.
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In the paper
“Histological examination of the skin showed numerous foam cells, cholesterol clefts, and neutrophils in the hypodermis (Fig. 3 D).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Delayed clearance of VLDL and spontaneous atherosclerosis.
plainn = 2- Asserted: passes — The authors put it forward as true.
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In the paper
“The lipoproteins in the HDL range were larger as judged by a shift in the HDL cholesterol peak.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Distribution of lipids and lipoproteins.
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In the paper
“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.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Abstract
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- Also stated in: § Delayed clearance of VLDL and spontaneous atherosclerosis. · plain
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“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).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Distribution of lipids and lipoproteins.
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“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.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Delayed clearance of VLDL and spontaneous atherosclerosis.
plaindirectn = 9- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Results
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In the paper
“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.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Delayed clearance of VLDL and spontaneous atherosclerosis.
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In the paper
“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 ).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Delayed clearance of VLDL and spontaneous atherosclerosis.
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In the paper
“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.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Distribution of lipids and lipoproteins.
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In the paper
“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).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Delayed clearance of VLDL and spontaneous atherosclerosis.
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In the paper
“The amount of apoB100 in the LDL fraction of 2/2 mice was similar to that in the 3/3 mice (data not shown).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Distribution of lipids and lipoproteins.
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In the paper
“Fig. 3 A shows a representative section with plaques composed mainly of foam cells and some fibrous caps.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Delayed clearance of VLDL and spontaneous atherosclerosis.
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In the paper
“ApoB48 was increased equally in both VLDL and IDL-LDL fractions, while the increase in apoB100 was mainly in the VLDL fraction.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Distribution of lipids and lipoproteins.
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In the paper
“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.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Distribution of lipids and lipoproteins.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Delayed clearance of VLDL and spontaneous atherosclerosis.
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In the paper
“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).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Delayed clearance of VLDL and spontaneous atherosclerosis.
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In the paper
“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).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Delayed clearance of VLDL and spontaneous atherosclerosis.
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In the paper
“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.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Distribution of lipids and lipoproteins.
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In the paper
“ApoE2 was associated with lipoproteins in the VLDL-IDL range, and appeared as two distinct peaks (fractions 15 and 20) by FPLC analysis.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Distribution of lipids and lipoproteins.
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In the paper
“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.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Distribution of lipids and lipoproteins.
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In the paper
“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).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Delayed clearance of VLDL and spontaneous atherosclerosis.
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In the paper
“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).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Introduction
What the sources say
- Not matchedcites [1]
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In the paper
“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.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Discussion
What the sources say
- Not matchedcites [23]
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In the paper
“Thus, a diet high in fat and cholesterol exacerbates the hyperlipidemia as well as development of atherosclerosis in the 2/2 animals.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Delayed clearance of VLDL and spontaneous atherosclerosis.
plaindirectn = 2- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Delayed clearance of VLDL and spontaneous atherosclerosis.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“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).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Discussion
What the sources say
- Not matchedcites [23]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“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).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Discussion
What the sources say
- Not matchedcites [1]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirectn = 2- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“The majority of apoE2 homozygotes have below average plasma cholesterol levels, but 5-10% of homozygotes develop type III HLP.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Introduction
What the sources say
- Not matchedcites [3]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
In the paper
“Thus, additional genetic, hormonal, or environmental factors are required to precipitate the disease (3).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Introduction
What the sources say
- Not matchedcites [3]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
In the paper
“For example, transgenic mice expressing low levels of human apoE2 are hypolipidemic, while those expressing high levels are hyperlipidemic (7).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Introduction
What the sources say
- Not matchedcites [7]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“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.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Introduction
What the sources say
- Not matchedcites [4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [5]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [6]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
In the paper
“(a ratio Ͼ 0.3 is diagnostic for type III HLP in humans [15]).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Distribution of lipids and lipoproteins.
What the sources say
- Not matchedcites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Another distinguishing characteristic of patients with type III HLP is the presence of planar and dermal xanthomas (20,21).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Delayed clearance of VLDL and spontaneous atherosclerosis.
What the sources say
- Not matchedcites [20]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [21]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
In the paper
“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).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Distribution of lipids and lipoproteins.
What the sources say
- Not matchedcites [19]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelationaln = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
- Not matched
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Additionally, the presence of endogenous mouse apoE protein in some cases complicates the interpretation of the phenotype.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Introduction
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“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).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Introduction
What the sources say
- Not matchedcites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Discussion
hedgedconditionaln = 2- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Discussion
What the sources say
- Not matchedcites [1]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
In the paper
“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.”
§ Type III Hyperlipoproteinemia and Spontaneous Atherosclerosis in Mice Resulting from Gene Replacement of Mouse Apoe with Human APOE * 2 > Discussion
What the sources say
- Not matchedcites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirectn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
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).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“APOE ε2-TR or APOE ε4-TR mice retain regulatory sequences of the mouse Apoe gene and the noncoding murine exon 1 surrounding the inserted human exons 2′, 3′, and 4′ [17,18] and therefore, they express the human apoE protein at physiological levels.”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [17]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“E2-TR mice display a plasma lipid profile similar to the type III hyperlipoproteinemia found in ~5–10% of E2/E2 humans, particularly when challenged with a high-fat diet (HFD)20.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [20]
The cited source says what the claim attributes to it.
In the citing paper
“Because Sullivan et al.20 reported HLP-III-like plasma lipids in E2-TR mice”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as Sullivan et al.20
The cited source says what the claim attributes to it.
In the citing paper
“These findings are consistent with type III hyperlipoproteinemia, previously described in human APOE ε2-TR mice [17].”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [17]
The cited source says what the claim attributes to it.
In the citing paper
“APOE ε2 targeted replacement mice develop type III hyperlipoproteinemia and spontaneous atherosclerosis [16] as well as volume overload as a function of their obesity, all of which are recognized vascular risk factors and may explain increased preponderance to thalamic localization of hemosiderin deposits in APP/ε2 mice found in our study.”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [16]
The cited source says what the claim attributes to it.
In the citing paper
“APOE ε2 targeted replacement mice develop type III hyperlipoproteinemia and spontaneous atherosclerosis [16] as well as volume overload as a function of their obesity, all of which are recognized vascular risk factors and may explain increased preponderance to thalamic localization of hemosiderin deposits in APP/ε2 mice found in our study.”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [16]
Citations
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Self-citationTransgenic mice carrying the apolipoprotein E3-Leiden gene exhibit hyperlipoproteinemia
van den Maagdenberg, A. M. J. M., Hofker, M. H., Krimpenfort, P., de Bruijn, I., van Vlijmen, B. J. M., van der Boom, H., Havekes, L. M., & Frants, R. R. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82232-3 · Cited by 229
Type III Hyperlipoproteinemia: Diagnosis, Molecular Defects, Pathology, and Treatment
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Xanthomatosis and Hyperlipoproteinemia
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Cited by
Sorted by citations
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661
“Although transgenic mouse models have been useful for investigating the role of human apoE isoforms in AD, the generation of apoE knock-in mice that express human apoE isoforms under the control of endogenous mouse regulatory elements allows one to examine the role of each isoform under more physiological conditions (…”
BackgroundMouse Models for Atherosclerosis and Pharmaceutical Modifiers
Zadelaar, S., Kleemann, R., Verschuren, L., der Weij, J. D. V.-V., van der Hoorn, J., Princen, H. M. G., & Kooistra, T. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.107.142570 · Cited by 526
Molecular Biology of Atherosclerosis
Hopkins, P. N. (2013) · Physiological Reviews · doi:10.1152/physrev.00004.2012 · Cited by 469
Practical considerations for choosing a mouse model of Alzheimer’s disease
Jankowsky, J. L., & Zheng, H. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0231-7 · Cited by 449
“Bruce Lamb’s group created APOEε2, ε3 and ε4 knock-in mice by targeting human ε2, ε3, and ε4 cDNAs in-frame into the endogenous mouse ApoE gene [197].”
Staels, B., Rubenstrunk, A., Noel, B., Rigou, G., Delataille, P., Millatt, L. J., Baron, M., Lucas, A., Tailleux, A., Hum, D. W., et al. (2013) · Hepatology · doi:10.1002/hep.26461 · Cited by 414
Metadata
- 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
- Published
- 1998-07-01
- Volume
- 102
- Issue
- 1
- Pages
- 130-135
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC509074
- OpenAlex
- W2009182898
- Semantic Scholar
- 5c70c14be49e1fca602aaf2a63c7aa5e2341ef41
- Cited by
- 264
- References
- 33
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 10 · 2023: 19 · 2022: 15 · 2021: 9 · 2020: 10 · 2019: 7 · 2018: 3 · 2017: 6 · 2016: 6 · 2015: 9 · 2014: 16 · 2013: 11 · 2012: 14
- FWCI
- 2.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL 42630)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-11, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-11 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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