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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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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.
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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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Results · plain
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
“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
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Also stated in: § Delayed clearance of VLDL and spontaneous atherosclerosis. · plain
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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Discussion · boosted
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
“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.
Strength:plain· not yet calibratedn = 3Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“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.
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“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.
Strength:plain· not yet calibratedn = 2Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“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.
Strength:plain· not yet calibratedn = 2Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“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.
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- The quote only partly states this claim. 3
- It may state two separate claims as one. 27
- Probably not a substantial claim. 10
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
“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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
- Also stated in: § Delayed clearance of VLDL and spontaneous atherosclerosis. · plain
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
“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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
“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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“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.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“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.
Strength:plain· not yet calibratedn = 2Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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
“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.
Strength:plain· not yet calibratedn = 2Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe quote only partly states this claim.
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
“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.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
“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.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
“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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“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.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“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.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
“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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“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.
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
“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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. 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
“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]
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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- 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
“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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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.
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
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- 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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-citationFat Transport in Lipoproteins — An Integrated Approach to Mechanisms and Disorders
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Flagged first, then by citations
2 of the 33 references couldn’t be matched to a known paper.
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
APOE genotype-specific differences in the innate immune response
Vitek, M. P., Brown, C. M., & Colton, C. A. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.11.014 · Cited by 362
Postprandial lipoprotein metabolism and atherosclerosis.
Karpe, F. (1999) · Journal of Internal Medicine · doi:10.1046/j.1365-2796.1999.00548.x · Cited by 360
Apo E structure determines VLDL clearance and atherosclerosis risk in mice
Knouff, C., Hinsdale, M. E., Mezdour, H., Altenburg, M. K., Watanabe, M., Quarfordt, S. H., Sullivan, P. M., & Maeda, N. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6172 · Cited by 324
Self-citationAPOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease
Youmans, K. L., Tai, L. M., Nwabuisi-Heath, E., Jungbauer, L., Kanekiyo, T., Gan, M., Kim, J., Eimer, W. A., Estus, S., Rebeck, G. W., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.407957 · Cited by 268
Shiri-Sverdlov, R., Wouters, K., Gorp, P. J. V., Gijbels, M. J., Noel, B., Buffat, L., Staels, B., Maeda, N., Bilsen, M. V., & Hofker, M. H. (2006) · Journal of Hepatology · doi:10.1016/j.jhep.2005.10.033 · Cited by 241
“Similar to humans, APOE2KI mice are responsive to lipid-lowering drugs such as fibrates, ligands for PPARa [3].”
BackgroundResultInfluentialSelf-citationMouse Models of Atherosclerosis
Daugherty, A. (2002) · The American Journal of the Medical Sciences · doi:10.1097/00000441-200201000-00002 · Cited by 218
Lee, S., Devanney, N. A., Golden, L. R., Smith, C. T., Schwartz, J. L., Walsh, A. E., Clarke, H. A., Goulding, D. S., Allenger, E. J., Morillo-Segovia, G., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112196 · Cited by 203
Dodart, J.-C., Marr, R. A., Koistinaho, M., Gregersen, B. M., Malkani, S., Verma, I. M., & Paul, S. M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409072102 · Cited by 207
Introduction of human apolipoprotein E4 “domain interaction” into mouse apolipoprotein E
Raffaı̈, R. L., Dong, L., Farese, R. V., & Weisgraber, K. H. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.201279298 · Cited by 201
Multifaceted roles of APOE in Alzheimer disease
Jackson, R. J., Hyman, B. T., & Serrano-Pozo, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00988-2 · Cited by 193
Abderrazak, A., Couchie, D., Mahmood, D. F. D., Elhage, R., Vindis, C., Laffargue, M., Mateo, V., Büchele, B., Ayala, M. R., Gaafary, M. E., et al. (2015) · Circulation · doi:10.1161/circulationaha.114.013730 · Cited by 177
“Accordingly, their plasma cholesterol and triglyceride levels are 2 to 3 times those of normolipidemic mice.(34) These animals are markedly defective in clearing β-migrating verylow-density lipoprotein particles and spontaneously develop atherosclerotic plaques, even while on a regular diet.”
BackgroundBieghs, V., van Gorp, P. J., Wouters, K., Hendrikx, T., Gijbels, M. J., van Bilsen, M., Bakker, J. A., Binder, C. J., Lütjohann, D., Staels, B., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030668 · Cited by 175
“The PLoS ONE | www.plosone.org 1 January 2012 | Volume 7 | Issue 1 | e30668 APOE2 protein has a markedly reduced affinity for the LDL receptor, leading to a plasma lipoprotein profile resembling human type III hyperlipoproteinaemia (HLP) [10].”
BackgroundInfluentialApoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function
Koizumi, K., Hattori, Y., Ahn, S. J., Buendia, I., Ciacciarelli, A., Uekawa, K., Wang, G., Hiller, A., Zhao, L., Voss, H. U., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06301-2 · Cited by 179
Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease
Williams, T., Borchelt, D., & Chakrabarty, P. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-0358-9 · Cited by 172
Tai, L. M., Ghura, S., Koster, K. P., Liakaite, V., Maienschein‐Cline, M., Kanabar, P., Collins, N., Ben‐Aissa, M., Lei, A. Z., Bahroos, N., et al. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13072 · Cited by 165
“Indeed, in APOE-targeted replacement mice (APOE-TR) (Sullivan et al. 1997,1998), which express the h-APOE genotypes (see ‘APOE-modulated inflammation: current perspective’), peritoneal LPS injection results in thermal dysregulation (in this case hypothermia), higher plasma © 2015 The Authors.”
Wouters, K., Shiri-Sverdlov, R., van Gorp, P. J., van Bilsen, M., & Hofker, M. H. (2005) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2005.085 · Cited by 163
Hu, J., Liu, C.-C., Chen, X.-F., Zhang, Y.-W., Xu, H., & Bu, G. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0001-3 · Cited by 161
“Given that apoE is produced predominantly by astrocytes in the brain [21], we investigated the impact of overexpressing different human apoE isoforms in astrocytes in apoE-TR mice, in which the coding region of the mouse endogenous Apoe gene was replaced with one of the three human APOE alleles without changing the re…”
BackgroundCohn, J. S., Marcoux, C., & Davignon, J. (1999) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.19.10.2474 · Cited by 156
Apolipoprotein E knock-out and knock-in mice: atherosclerosis, metabolic syndrome, and beyond
Pendse, A. A., Arbones-Mainar, J. M., Johnson, L. A., Altenburg, M. K., & Maeda, N. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r800070-jlr200 · Cited by 155
“In contrast, mice with human apoE2, which binds to LDLR with less affinity, accumulate plasma remnants with high cholesterol and triglycerides (TG) and develop atherosclerosis (16).”
BackgroundSelf-citationBour, A., Grootendorst, J., Vogel, E., Kelche, C., Dodart, J.-C., Bales, K., Moreau, P.-H., Sullivan, P. M., & Mathis, C. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.05.008 · Cited by 141
Self-citationCOLTON, C., BROWN, C., COOK, D., NEEDHAM, L., XU, Q., CZAPIGA, M., SAUNDERS, A., SCHMECHEL, D., RASHEED, K., & VITEK, M. (2002) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00016-7 · Cited by 108
Morikawa, M., Fryer, J. D., Sullivan, P. M., Christopher, E. A., Wahrle, S. E., DeMattos, R. B., O'Dell, M. A., Fagan, A. M., Lashuel, H. A., Walz, T., et al. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.11.005 · Cited by 126
“Animals APOE knock-in mice expressing human apoE2, apoE3, or apoE4 (homozygous) under the control of the endogenous mouse apoE promoter were generated by a gene replacement strategy (Knouff et al., 1999; Sullivan et al., 1997, 1998).”
Self-citationLauderback, C. M., Kański, J., Hackett, J. M., Maeda, N., Kindy, M. S., & Butterfield, D. A. (2002) · Brain Research · doi:10.1016/s0006-8993(01)03228-0 · Cited by 134
Self-citationGenetic and Diet-Induced Animal Models for Non-Alcoholic Fatty Liver Disease (NAFLD) Research
Flessa, C., Ansari, N. N., Kyrou, I., Leca, B. M., Lianou, M., Chatzigeorgiou, A., Kaltsas, G., Kassi, E. N., & Randeva, H. S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232415791 · Cited by 141
“The Apolipoprotein E2 (APOE2) knock-in (APOE2ki) mouse model was generated when the murine Apoe gene was replaced by a human Apolipoprotein E2 (APOE*2) gene allele via targeted gene replacement in embryonic stem cells and was first used as a model for hyperlipoproteinemia and atherosclerosis [74].”
Method25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner
Wong, M. Y., Lewis, M., Doherty, J. J., Shi, Y., Cashikar, A. G., Amelianchik, A., Tymchuk, S., Sullivan, P. M., Qian, M., Covey, D. F., et al. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01869-3 · Cited by 121
“Microglia were prepared from neonatal mice expressing 222 human APOE2 (E2), APOE3 (E3), or APOE4 (E4) at the mouse APOE locus (56-58).”
Self-citationMarked regional differences of brain human apolipoprotein e expression in targeted replacement mice
Sullivan, P. M., Mace, B. E., Maeda, N., & Schmechel, D. E. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2003.10.011 · Cited by 113
Self-citationHadri, K. E., Mahmood, D. F. D., Couchie, D., Jguirim-Souissi, I., Genze, F., Diderot, V., Syrovets, T., Lunov, O., Simmet, T., & Rouis, M. (2012) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.112.249334 · Cited by 118
“Accordingly, their plasma cholesterol and triglyceride levels are 2 to 3 those of normolipidemic mice.(42) These animals are markedly defective in clearing -migrating very- lowdensity lipoprotein particles, and spontaneously develop atherosclerotic plaques, even on a regular diet.”
BackgroundHumanising the mouse genome piece by piece
Zhu, F., Nair, R., Fisher, E., & Cunningham, T. J. (2019) · Nature Communications · doi:10.1038/s41467-019-09716-7 · Cited by 114
Mouse models of hyperlipidemia and atherosclerosis
Fazio, S. (2001) · Frontiers in bioscience · doi:10.2741/fazio · Cited by 114
“Exchanging the human apoE2 gene for the mouse apoE gene produces features of type III hyperlipoproteinemia and spontaneous atherosclerosis (32).”
BackgroundMethodReduced levels of human apoE4 protein in an animal model of cognitive impairment
Sullivan, P. M., Han, B., Liu, F., Mace, B. E., Ervin, J. F., Wu, S., Koger, D., Paul, S., & Bales, K. R. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2009.05.011 · Cited by 113
Self-citationMaezawa, I., Nivison, M. P., Montine, K. S., Maeda, N., & Montine, T. J. (2006) · The FASEB Journal · doi:10.1096/fj.05-5423fje · Cited by 117
“Here we used TR APOE mice that express “humanized” apoE isoforms under control of endogenous promoters and repressors to more closely reflect the appropriate expression of apoE in the various cells of brain (34, 35).”
MethodSelf-citationWu, Y., Waite, L. L., Jackson, A., Sheu, W. H., Buyske, S. G., Absher, D., Arnett, D. K., Boerwinkle, E., Bonnycastle, L. L., Carty, C. L., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003379 · Cited by 112
“APOE: rs769455 (R163C) [31] Yes rs769455 2nd AA 0.”
Wouters, K., van Bilsen, M., van Gorp, P. J., Bieghs, V., Lütjohann, D., Kerksiek, A., Staels, B., Hofker, M. H., & Shiri-Sverdlov, R. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.01.046 · Cited by 109
“APOE2 has a markedly reduced affinity for the LDL receptor, leading to a plasma lipoprotein profile resembling human type III hyperlipoproteinemia [5].”
BackgroundMouse models of atherosclerosis in translational research
Ilyas, I., Little, P. J., Liu, Z., Xu, Y., Kamato, D., Berk, B. C., Weng, J., & Xu, S. (2022) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2022.06.009 · Cited by 124
APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations
Shinohara, M., Kanekiyo, T., Yang, L., Linthicum, D., Shinohara, M., Fu, Y., Price, L., Frisch‐Daiello, J. L., Han, X., Fryer, J. D., et al. (2016) · Annals of Neurology · doi:10.1002/ana.24628 · Cited by 111
Common germline variants of the human APOE gene modulate melanoma progression and survival
Ostendorf, B. N., Bilanovic, J., Adaku, N., Tafreshian, K. N., Tavora, B., Vaughan, R. D., & Tavazoie, S. F. (2020) · Nature Medicine · doi:10.1038/s41591-020-0879-3 · Cited by 108
Johnson, L. A., Olsen, R. H. J., Merkens, L. S., DeBarber, A., Steiner, R. D., Sullivan, P. M., Maeda, N., & Raber, J. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.12.016 · Cited by 107
“…the apoE isoforms differentially impact the expression and function of apoE in humans and in mice (Betrand et al., 1995, Beffert et al., 1999, Fryer et al., 2005, Fukomoto et al., 2003, Glockner et al., 2002, Poirer et al., 2005, Ramaswamy et al., 2005, Riddell et al., 2008, Sullivan et al., 2004).”
Self-citationSabo, T., Lomnitski, L., Nyska, A., Beni, S., Maronpot, R. R., Shohami, E., Roses, A. D., & Michaelson, D. M. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00438-3 · Cited by 104
Cariello, M., Piccinin, E., & Moschetta, A. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.01.012 · Cited by 108
Keene, C. D., Cudaback, E., Li, X., Montine, K. S., & Montine, T. J. (2011) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2011.08.002 · Cited by 103
Duff, K. (2004) · Briefings in Functional Genomics and Proteomics · doi:10.1093/bfgp/3.1.47 · Cited by 98
Akiyama, T. E., Lambert, G., Nicol, C. J., Matsusue, K., Peters, J. M., Brewer, H. B., & Gonzalez, F. J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312802200 · Cited by 97
Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice
Hamanaka, H. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.3.353 · Cited by 99
“(29,30) pioneered the generation of human apoE3 and apoE2 mice, and Knouff et al.”
EFAD transgenic mice as a human APOE relevant preclinical model of Alzheimerʼns disease
Tai, L. M., Balu, D., Avila-Munoz, E., Abdullah, L., Thomas, R., Collins, N., Valencia-Olvera, A. C., & LaDu, M. J. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r076315 · Cited by 93
“(32, 78) via a contract with Taconic Biosciences(2).”
MethodFarmer, B. C., Williams, H. C., Devanney, N. A., Piron, M. A., Nation, G. K., Carter, D. J., Walsh, A. E., Khanal, R., Young, L. E. A., Kluemper, J. C., et al. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00483-y · Cited by 87
Bharti, K., den Hollander, A. I., Lakkaraju, A., Sinha, D., Williams, D. S., Finnemann, S. C., Rickman, C. B., Malek, G., & D'Amore, P. A. (2022) · Experimental Eye Research · doi:10.1016/j.exer.2022.109170 · Cited by 98
Kuszczyk, M. A., Sanchez, S., Pankiewicz, J., Kim, J., Duszczyk, M., Guridi, M., Asuni, A. A., Sullivan, P. M., Holtzman, D. M., & Sadowski, M. J. (2013) · The American Journal of Pathology · doi:10.1016/j.ajpath.2013.01.034 · Cited by 89
“These Tg mice were derived from ApoE-TR mice, where human ApoE isoforms are expressed at the physiological levels of murine ApoE expression.(18,19) For the first time, we have quantified deposition of extracellular Ab in these previously uncharacterized AD Tg mice lines, calculating the average load of fibrillar Ab de…”
BackgroundSelf-citationGetz, G. S., & Reardon, C. A. (2016) · Journal of Lipid Research · doi:10.1194/jlr.r067249 · Cited by 90
The benefit of docosahexaenoic acid for the adult brain in aging and dementia
Salem, N., Vandal, M., & Calon, F. (2014) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2014.10.003 · Cited by 86
Apolipoprotein E in Cardiometabolic and Neurological Health and Diseases
Alagarsamy, J., Jaeschke, A., & Hui, D. Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179892 · Cited by 86
“Likewise, while most of the ε2 carriers in humans have normal or low plasma cholesterol levels and have lower risk of coronary atherosclerosis, with only a subset of individuals developing dysbetalipoproteinemia, all human APOE2 gene replacement mice displayed high plasma cholesterol and triglyceride levels with spont…”
BackgroundAPOE ε 4 is associated with higher vitamin D levels in targeted replacement mice and humans
Huebbe, P., Nebel, A., Siegert, S., Moehring, J., Boesch, C., Most, E., Pallauf, J., Egert, S., Müller, M. J., Schreiber, S., et al. (2011) · The FASEB Journal · doi:10.1096/fj.11-180935 · Cited by 83
“ε2 115 (8) 7 (4) ε3 1078 (77) 146 (78) ε4 205 (15) 33 (18) ε2ε2 2 ( 1) 0 (0) ε2ε3 92 (13) 3 (3) ε2ε4 19 (3) 4 (4) ε3ε3 410 (59) 60 (65) ε3ε4 166 (24) 23 (25) ε4ε4 10 (1) 3 (3) ε4-Carrier 195 (28) 30 (32)”
APOE2 is associated with longevity independent of Alzheimer’s disease
Shinohara, M., Kanekiyo, T., Tachibana, M., Kurti, A., Shinohara, M., Fu, Y., Zhao, J., Han, X., Sullivan, P. M., Rebeck, G. W., et al. (2020) · eLife · doi:10.7554/elife.62199 · Cited by 82
Self-citationApolipoprotein E-specific innate immune response in astrocytes from targeted replacement mice
Maezawa, I., Maeda, N., Montine, T. J., & Montine, K. S. (2006) · Journal of Neuroinflammation · doi:10.1186/1742-2094-3-10 · Cited by 83
“Maeda and colleagues [34,35].”
Self-citationHennuyer, N., Tailleux, A., Torpier, G., Mezdour, H., Fruchart, J., Staels, B., & Fiévet, C. (2005) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000175756.56818.ee · Cited by 76
Self-citationLalloyer, F., Wouters, K., Baron, M., Caron, S., Vallez, E., Vanhoutte, J., Baugé, E., Shiri‐Sverdlov, R., Hofker, M. H., Staels, B., et al. (2011) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.110.220525 · Cited by 75
APOE genotype-specific differences in human and mouse macrophage nitric oxide production
Colton, C. A., Needham, L. K., Brown, C., Cook, D., Rasheed, K., Burke, J. R., Strittmatter, W. J., Schmechel, D. E., & Vitek, M. P. (2004) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2003.10.015 · Cited by 75
Lalloyer, F., Fiévet, C., Lestavel, S., Torpier, G., van der Veen, J., Touche, V., Bultel, S., Yous, S., Kuipers, F., Paumelle, R., et al. (2006) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000248101.93488.84 · Cited by 68
Sex- and APOE Isoform-Dependent Effects of Radiation on Cognitive Function
Villasana, L., Acevedo, S. F., Poage, C. T., & Raber, J. (2006) · Radiation Research · doi:10.1667/rr0642.1 · Cited by 74
Lewandowski, C. T., Maldonado Weng, J., & LaDu, M. J. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104811 · Cited by 72
Kajiwara, Y., Franciosi, S., Takahashi, N., Krug, L., Schmeidler, J., Taddei, K., Haroutunian, V. H., Fried, U., Ehrlich, M. E., Martins, R. N., et al. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-1 · Cited by 72
“These mice have been previously described [46-50].”
Sex steroids, APOE genotype and the innate immune system
Colton, C. A., Brown, C. M., & Vitek, M. P. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.08.001 · Cited by 71
ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations
Johnson, L. A., Zuloaga, D. G., Bidiman, E., Marzulla, T., Weber, S., Wahbeh, H., & Raber, J. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.95 · Cited by 69
The structure and function of Niemann–Pick C1-like 1 protein
Yu, L. (2008) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e3282f9b563 · Cited by 70
The APOE4 genotype alters the response of microglia and macrophages to 17β-estradiol
Brown, C. M., Choi, E., Xu, Q., Vitek, M. P., & Colton, C. A. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.04.018 · Cited by 67
Klein, R. C., Mace, B. E., Moore, S. D., & Sullivan, P. M. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.10.027 · Cited by 67
“hyperlipidemia (Sullivan et al., 1998), a chronic pro-inflammatory state that can confound interpretation of CNS phenotypes.”
Self-citationDetermination of the lower threshold of apolipoprotein E resulting in remnant lipoprotein clearance
Hasty, A. H., Linton, M. F., Swift, L. L., & Fazio, S. (1999) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)33397-6 · Cited by 68
Synergistic effects of APOE and sex on the gut microbiome of young EFAD transgenic mice
Weng, J. M., Parikh, I. J., Naqib, A. D., York, J. M., Green, S. J., Estus, S., & LaDu, M. J. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0352-2 · Cited by 65
Murine Gut Microbiome Association With APOE Alleles
Parikh, I. J., Estus, J. L., Zajac, D. J., Malik, M., Weng, J. M., Tai, L. M., Chlipala, G. E., LaDu, M. J., Green, S. J., & Estus, S. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00200 · Cited by 64
A Novel Role for CD36 in VLDL-Enhanced Platelet Activation
Englyst, N. A., Taube, J. M., Aitman, T. J., Baglin, T. P., & Byrne, C. D. (2003) · Diabetes · doi:10.2337/diabetes.52.5.1248 · Cited by 59
“VLDL is present in the atherosclerotic plaque (27), and both humans and mice with type III hyperlipidemia apoE2/E2 homozygosity have increased levels of VLDL and remnant triglyceride-rich lipoproteins (28).”
BackgroundAPOE genotype affects the pre‐synaptic compartment of glutamatergic nerve terminals
Dumanis, S. B., DiBattista, A. M., Miessau, M., Moussa, C. E. H., & Rebeck, G. W. (2013) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07908.x · Cited by 55
Hepatic Catabolism of Remnant Lipoproteins: Where the Action Is
Havel, R. J., & Hamilton, R. L. (2004) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000115382.53810.24 · Cited by 59
Arold, S. P., Sullivan, P. M., Bilousova, T. V., Teng, E., Miller, C. A., Poon, W. W., Vinters, H. V., Cornwell, L. B., Saing, T., Cole, G. M., et al. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0892-1 · Cited by 58
“Heterozygous apoE2/4 mice were used because type III hyperlipoproteinemia has been demonstrated in homozygous animals [63].”
Self-citationPankiewicz, J. E., Guridi, M., Kim, J., Asuni, A. A., Sanchez, S., Sullivan, P. M., Holtzman, D. M., & Sadowski, M. J. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0075-0 · Cited by 57
Self-citationJun, J., Lee, J. H., Jia, Y., Hoang, M.-H., Byun, H., Kim, K. H., & Lee, S. (2012) · Journal of Nutrition · doi:10.3945/jn.111.152538 · Cited by 55
“APOE2 mice develop extreme hypertriglyceridemia, accumulating TG-rich lipoproteins in the plasma (22).”
BackgroundSharman, M. J., Morici, M., Hone, E., Berger, T., Taddei, K., Martins, I. J., Lim, W. L. F., Singh, S., Wenk, M. R., Ghiso, J., et al. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-100141 · Cited by 54
“However, a confounding factor when interpreting the results in the APOE knock-in mice is the higher plasma ApoE levels observed in ε2 mice, which can be up to approximately 15 times greater than ε3 and ε4mice [9,11].”
Li, X., Montine, K. S., Keene, C. D., & Montine, T. J. (2015) · The FASEB Journal · doi:10.1096/fj.14-262683 · Cited by 54
Tsukamoto, K., Maugeais, C., Glick, J. M., & Rader, D. J. (2000) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32059-9 · Cited by 52
Apolipoprotein‐E Allele‐Specific Regulation of Nitric Oxide Production
Colton, C. A., Brown, C. M., Czapiga, M., & Vitek, M. P. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb04070.x · Cited by 52
Carmona, M. C., Louche, K., Lefebvre, B., Pilon, A., Hennuyer, N., Audinot-Bouchez, V., Fiévet, C., Torpier, G., Formstecher, P., Renard, P., et al. (2007) · Diabetes · doi:10.2337/db06-1734 · Cited by 51
“These mice express human apoE2 instead of mouse apoE (43).”
BackgroundMaezawa, I., Jin, L., Woltjer, R. L., Maeda, N., Martin, G. M., Montine, T. J., & Montine, K. S. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02818.x · Cited by 51
“Homozygous APOE2, APOE3 and APOE4 targeted replacement (TR) mice ‘humanized’ at apoE were developed by Dr Maeda and colleagues (Sullivan et al. 1997; Sullivan et al. 1998).”
BackgroundSelf-citationMann, K. M. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh199 · Cited by 48
“It has been suggested by Sullivan et al. and others (51,54) that this condition manifests itself in 1 2 KI mice owing to the presence of additional genetic factors in the mouse genome that interact with the 1 2 allele.”
BackgroundMethodHuman apoE3 but not apoE4 rescues impaired astrocyte activation in apoE null mice
Ophir, G., Meilin, S., Efrati, M., Chapman, J., Karussis, D., Roses, A. D., & Michaelson, D. M. (2003) · Neurobiology of Disease · doi:10.1016/s0969-9961(02)00005-0 · Cited by 49
Comhair, T. M., Garcia‐Caraballo, S., Dejong, C. H. C., Lamers, W. H., & Köhler, E. S. (2011) · Nutrition & Metabolism · doi:10.1186/1743-7075-8-4 · Cited by 45
“The replacement of the mouse Apoe gene with the human APOE2 allele in APOE2ki mice decreases the hepatic uptake of (very) low-density lipoproteins and, thus, causes mixed hyperlipidemia [13].”
BackgroundMethodHarmful Effects of Increased LDLR Expression in Mice With Human APOE*4 But Not APOE*3
Malloy, S. I., Altenburg, M. K., Knouff, C., Lanningham-Foster, L., Parks, J. S., & Maeda, N. (2004) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000094963.07902.fb · Cited by 37
“F 66 3 (18) 106 10 (9) 40 4 (18) 39 6 (9) 49 7 (5) 81 10 (9)”
Self-citationEmergence of a seizure phenotype in aged apolipoprotein epsilon 4 targeted replacement mice
Hunter, J. M., Cirrito, J. R., Restivo, J. L., Kinley, R. D., Sullivan, P. M., Holtzman, D. M., Koger, D., Delong, C., Lin, S., Zhao, L., et al. (2012) · Brain Research · doi:10.1016/j.brainres.2012.05.048 · Cited by 45
Self-citationChin, D., Hagl, S., Höhn, A., Huebbe, P., Pallauf, K., Grune, T., Frank, J., Eckert, G. P., & Rimbach, G. H. (2014) · Genes & Nutrition · doi:10.1007/s12263-014-0397-3 · Cited by 43
A multi‐hit hypothesis for an APOE4 ‐dependent pathophysiological state
Steele, O. G., Stuart, A. C., Minkley, L., Shaw, K., Bonnar, O., Anderle, S., Penn, A. C., Rusted, J., Serpell, L., Hall, C., et al. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15685 · Cited by 44
“Much of the supporting work has been performed in cell and animal model systems such as the targeted replacement (TR) mice, in which the mouse Apoe gene is replaced with human APOE (Knouff et al., 1999; Sullivan et al., 1997, 1998, 2004).”
BackgroundUses for humanised mouse models in precision medicine for neurodegenerative disease
Nair, R., Corrochano, S., Gasco, S., Tibbit, C., Thompson, D., Maduro, C., Ali, Z., Fratta, P., Acevedo‐Arozena, A., Cunningham, T. J., et al. (2019) · Mammalian Genome · doi:10.1007/s00335-019-09807-2 · Cited by 43
Kuhel, D. G., Konaniah, E. S., Basford, J. E., McVey, C. M., Goodin, C., Chatterjee, T. K., Weintraub, N. L., & Hui, D. Y. (2012) · Diabetes · doi:10.2337/db12-0390 · Cited by 45
“APOE3 gene (24,25), hereafter designated as APOE2 and APOE3 mice, were”
BackgroundNeuronal ApoE4 in Alzheimer’s disease and potential therapeutic targets
Zhang, L., Xia, Y., & Gui, Y. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1199434 · Cited by 41
“ApoE is a lipid transporter, a 299-amino acid protein with a molecular weight of 34 kDa (Sullivan et al., 1998; Guo et al., 2020).”
BackgroundCanesi, F., Mateo, V., Couchie, D., Karabina, S., Nègre‐Salvayre, A., Rouis, M., & Hadri, K. E. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy183 · Cited by 40
Effect of human apolipoprotein E genotype on the pathogenesis of experimental ocular HSV-1
Bhattacharjee, P. S., Neumann, D. M., Foster, T. P., Bouhanik, S., Clément, C., Vinay, D. S., Thompson, H. W., & Hill, J. M. (2008) · Experimental Eye Research · doi:10.1016/j.exer.2008.05.007 · Cited by 40
“Levels of expression of apoE3 or apoE4 have been characterized and are not significantly different between the apoE3 TR and apoE4 TR mice (Brown et al., 2002; Knouff et al., 1999; Piedrahita et al., 1992; Sullivan et al., 1997; Sullivan et al., 1998).”
BackgroundAtheroprotective Effect of Human Apolipoprotein A5 in a Mouse Model of Mixed Dyslipidemia
Mansouri, R. M., Baugé, E., Gervois, P. P., Fruchart‐Najib, J., Fiévet, C., Staels, B., & Fruchart, J. (2008) · Circulation Research · doi:10.1161/circresaha.108.179861 · Cited by 40
Kim, J. H., Lee, S., Kim, K., Yu, Y. S., & Kim, J. H. (2012) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2012.02.005 · Cited by 41
ApoE genotype-specific inhibition of apoptosis
DeKroon, R. M., Mihovilovic, M., Goodger, Z. V., Robinette, J. B., Sullivan, P. M., Saunders, A. M., & Strittmatter, W. J. (2003) · Journal of Lipid Research · doi:10.1194/jlr.m300097-jlr200 · Cited by 40
“Since apoE protein levels, lipid levels (cholesterol, triglycerides), and the distribution of lipoprotein classes (VLDL, IDL/LDL, HDL) vary with APOE genotype (12, 13, 20, 21 ), lipoprotein concentrations for each APOE genotype”
BackgroundMethodSelf-citation
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
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