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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1567.)
© 2001 American Heart Association, Inc.

Brief Review

Lipoprotein Size and Atherosclerosis Susceptibility in Apoe^-/- and Ldlr^-/- Mice

Murielle M. Véniant; Shannon Withycombe; Stephen G. Young

From Amgen Inc (M.M.V.), Thousand Oaks, Calif; the Gladstone Institute of Cardiovascular Disease (S.W., S.G.Y.), University of California, San Francisco; the Cardiovascular Research Institute (S.G.Y.), University of California, San Francisco; and the Department of Medicine (S.G.Y.), University of California, San Francisco, and the Medical Service (S.G.Y.), San Francisco General Hospital, San Francisco, Calif.

Correspondence to Stephen G. Young, MD, or Murielle Véniant, PhD, Gladstone Institute of Cardiovascular Disease, PO Box 419100, San Francisco, CA 94141-9100. E-mail syoung{at}gladstone.ucsf.edu or mveniant@amgen.com

	Abstract

Top Abstract Introduction Chow-Fed Apoe-/- and Ldlr-/-... Atherosclerosis Susceptibility... Are the Differences in... Implications for Studies of... Prospects for a Diet-Independent... References

 
Abstract—— Two hypercholesterolemic mouse models, the apo-E–deficient mouse (Apoe^-/-) and the LDL receptor–deficient mouse (Ldlr^-/-), have been used extensively as animal models of atherogenesis. Total plasma cholesterol levels in chow-fed Apoe^-/- mice are much higher than in Ldlr^-/- mice. In a recent study, we managed to even-up the cholesterol levels in Apoe^-/- mice and Ldlr^-/- mice by making both models homozygous for the Apob¹⁰⁰ (apo B-100–only) allele. On a chow diet, apo-E–deficient apo B-100–only mice (Apoe^-/-Apob^100/100) and LDL receptor–deficient apo B-100–only mice (Ldlr^-/-Apob^100/100) had similar total plasma cholesterol levels (300 mg/dL). The plasma of Ldlr^-/-Apob^100/100 mice contained large numbers of small lipoproteins, whereas the plasma of Apoe^-/-Apob^100/100 mice contained much lower levels of much larger lipoproteins. Interestingly, the Ldlr^-/-Apob^100/100 mice developed far more extensive atherosclerotic lesions than the Apoe^-/-Apob^100/100 mice. The finding of substantially more atherosclerosis in Ldlr^-/-Apob^100/100 mice than in Apoe^-/-Apob^100/100 mice, despite nearly identical cholesterol levels, suggests that large numbers of small apo B-100–containing lipoproteins are far more atherogenic than lower numbers of large apo B-100–containing lipoproteins.

Key Words: atherosclerosis • apolipoprotein B • LDL receptor • Cre recombinase • microsomal triglyceride transfer protein

	Introduction

Top Abstract Introduction Chow-Fed Apoe-/- and Ldlr-/-... Atherosclerosis Susceptibility... Are the Differences in... Implications for Studies of... Prospects for a Diet-Independent... References

 
Two hypercholesterolemic mouse models, the apo E–deficient mouse (Apoe^-/-)^1–3 and the LDL receptor–deficient mouse (Ldlr^-/-),⁴ have been used extensively to study atherogenesis. On a chow diet, Apoe^-/- mice have total cholesterol levels of 400 to 500 mg/dL due mainly to the accumulation of VLDL remnants and develop severe atherosclerotic lesions throughout the arterial tree.^5,6 Chow-fed Ldlr^-/- mice have mildly increased plasma cholesterol levels (175 to 225 mg/dL) from an accumulation of LDL and develop only minimal atherosclerotic lesions in the proximal aortic root.⁴ Apo B-48 is the predominant apolipoprotein in the VLDL remnants of Apoe^-/- mice, whereas apo B-100 predominates in the LDL of Ldlr^-/- mice.⁷

Both the Apoe^-/- and Ldlr^-/- mice have been a boon to atherosclerosis research, principally because they have made it possible to investigate a multitude of genetic influences on atherogenesis and to do so without resorting to diets containing high levels of fats and cholesterol. Nevertheless, reservations about these models are occasionally voiced at scientific meetings. In the case of chow-fed Ldlr^-/- mice, there is frustration about the minimal amount of atherosclerotic lesions, even after 9 to 12 months. In the case of the Apoe^-/- mice, concerns are voiced about the very high ("nonphysiological") plasma cholesterol levels. One also hears concerns about using an animal model in which most of the cholesterol is carried in apo B-48–containing VLDL and chylomicron remnants, given that most humans with atherosclerosis have high plasma levels of apo B-100–containing LDL.

In discussions of the pros and cons of Apoe^-/- and Ldlr^-/- mice, one occasionally hears speculation about whether the lipoproteins in the 2 animal models are intrinsically different in their capacities to promote atherosclerosis. Some investigators are convinced that the VLDL remnants in Apoe^-/- mice are particularly atherogenic, given the dramatic and severe atherosclerotic lesions in that model. Others have maintained that such speculation is pointless because the total plasma cholesterol levels in Apoe^-/- mice are so much higher than in Ldlr^-/- mice.

	Chow-Fed Apoe-/- and Ldlr-/- Mice With Similar Total Cholesterol Levels

Top Abstract Introduction Chow-Fed Apoe-/- and Ldlr-/-... Atherosclerosis Susceptibility... Are the Differences in... Implications for Studies of... Prospects for a Diet-Independent... References

 
In a recent study,⁸ we managed to even up the cholesterol levels in chow-fed Apoe^-/- mice and Ldlr^-/- mice. We did so by making both mouse models homozygous for the Apob¹⁰⁰ ("apo B-100–only") allele,⁹ which ameliorates the hypercholesterolemia in the setting of Apoe deficiency⁹ but worsens it in the setting of Ldlr deficiency.^8,10 Remarkably, the total plasma cholesterol levels in apo B-100–only, apo E–deficient mice (Apoe^-/-Apob^100/100 and apo B-100–only, LDL receptor–deficient mice (Ldlr^-/-Apob^100/100 were virtually identical (275 to 325 mg/dL).⁸ HDL cholesterol levels were also indistinguishable (Figure 1).

View larger version (23K): [in this window] [in a new window]   Figure 1. Distribution of cholesterol within the plasma lipoproteins of Apoe-/-Apob100/100 and Ldlr-/-Apob100/100 mice. The lipoproteins in mouse plasma were size fractionated on a Superose 6/600 column. Modified from an article by Véniant et al,8 with permission from the American Society of Clinical Investigation.

Although the total plasma cholesterol levels in Apoe^-/-Apob^100/100 and Ldlr^-/-Apob^100/100 mice were virtually identical, the sizes of lipoproteins in the 2 models were not.⁸ Nearly all of the cholesterol in the plasma of Apoe^-/-Apob^100/100 mice was in the VLDL fraction, whereas nearly all of the cholesterol in the Ldlr^-/-Apob^100/100 mice was in LDL (Figure 1). When we quantified the sizes of the lipoproteins, we found that the lipoproteins in the plasma of Apoe^-/-Apob^100/100 mice were immense (mean size of 63 nm), whereas the vast majority of the lipoproteins in Ldlr^-/-Apob^100/100 mice were small (mean size of only 24 nm). There was almost no overlap in the sizes of the apo B–containing lipoproteins in the plasma.

Finding identical cholesterol levels but differences in lipoprotein size implied that the numbers of particles in the plasma of the 2 models would be different. Indeed, this was the case. Plasma apo B-100 levels were nearly 4-fold higher in Ldlr^-/-Apob^100/100 mice than in Apoe^-/-Apob^100/100 mice.⁸ Thus, we had generated 2 new hypercholesterolemic mouse models—both apo B-100–only and both with the same plasma cholesterol level—but with profound differences in lipoprotein sizes and lipoprotein number.

	Atherosclerosis Susceptibility in Apoe-/-Apob100/100 and Ldlr-/-Apob100/100 Mice

Top Abstract Introduction Chow-Fed Apoe-/- and Ldlr-/-... Atherosclerosis Susceptibility... Are the Differences in... Implications for Studies of... Prospects for a Diet-Independent... References

 
We decided to study atherosclerosis susceptibility in Apoe^-/-Apob^100/100 and Ldlr^-/-Apob^100/100 mice to obtain insights into the relative atherogenicities of 2 very different lipoprotein phenotypes.⁸ For controls, we analyzed Apoe^-/- and Ldlr^-/- mice that were homozygous for a wild-type apo B allele (Apoe^-/-Apob^+/+ and Ldlr^-/-Apob^+/+ mice). All 4 groups of mice (n40 each) were fed a chow diet for 40 weeks. At the 40-week time point, the total plasma cholesterol levels (mean±SEM) in Apoe^-/-Apob^100/100 and Ldlr^-/-Apob^100/100 were virtually identical (334±12 and 336±8 mg/dL, respectively). As expected, the total plasma cholesterol levels were much higher in Apoe^-/-Apob^+/+ mice (497±23 mg/dL) and lower in Ldlr^-/-Apob^+/+ mice (235±12 mg/dL).

Computer-assisted morphometric techniques were used to assess the percentage of the aortic surface covered by atherosclerotic lesions at 40 weeks. The results were striking and clear. Mice with larger numbers of small lipoproteins (ie, the Ldlr^-/-Apob^100/100 mice) had far more atherosclerosis than did mice with smaller numbers of large lipoproteins (ie, the Apoe^-/-Apob^100/100 mice)⁸ (the Table). Of note, the Apoe^-/-Apob^+/+ mice actually had only about one half as much atherosclerosis as the Ldlr^-/-Apob^100/100 mice, despite having far higher plasma cholesterol levels. As expected, the Ldlr^-/-Apob^+/+ mice had minimal atherosclerosis.

View this table: [in this window] [in a new window]   Table 1. Measurements of Atherosclerosis in Apoe-/-Apob+/+, Apoe-/-Apob100/100, Ldlr-/-Apob+/+, and Ldlr-/-Apob100/100 Mice

We also measured the amount of free and esterified cholesterol in the aortas and the rate of aortic DNA synthesis. The Ldlr^-/-Apob^100/100 mice accumulated far more cholesterol in their aortas than did the Apoe^-/-Apob^100/100 mice (the Tabl1), despite virtually identical plasma cholesterol levels.⁸ We found a strong, positive correlation between lesion size, measured morphometrically, and the aortic content of esterified cholesterol both for all of the mice in the study (r=0.858, P<0.0001) and for most of the subgroups (Apoe^-/-Apob^+/+: r=0.719, P<0.0001; Apoe^-/-Apob^100/100: r=0.705, P<0.0001; and Ldlr^-/-Apob^100/100: r=0.734, P<0.0001). These results suggest that it would be reasonable to substitute lipid measurements for morphometric approaches in many mouse atherosclerosis experiments.

To measure DNA synthesis within the aortas, we used stable-isotope incorporation/mass spectrometry. In line with the morphometric results and the cholesterol measurements, aortic DNA synthesis in the Ldlr^-/-Apob^100/100 mice was almost twice as high as in Apoe^-/-Apob^100/100 mice⁸ (Table 1). However, the correlations between aortic DNA synthesis and the other measures of atherosclerosis were relatively low (r=0.574, P<0.0001 for DNA synthesis vs morphometric data; r=0.469, P<0.0001 for DNA synthesis vs aortic cholesterol esters). The correlation coefficients were far lower (generally 0.2 to 0.4) when the data from single genotypes were considered. We doubt that the weak correlations can be attributed to inaccuracy in the DNA synthesis rate, given the precision of mass spectrometry. One possible explanation for the low correlation coefficients is that we measured DNA synthesis in the whole aorta, thereby contaminating our measurements with populations of cells that were not directly involved in the atherosclerotic process. Alternatively, cellular proliferation and the accumulation of lipid-rich lesions may not be tightly linked at a mechanistic level, either temporally or spatially. We suspect that these issues could be sorted out with additional studies of aortic DNA synthesis in mice.

	Are the Differences in Atherosclerosis Susceptibility Explained by Differences in Lipoprotein Size and Number?

Top Abstract Introduction Chow-Fed Apoe-/- and Ldlr-/-... Atherosclerosis Susceptibility... Are the Differences in... Implications for Studies of... Prospects for a Diet-Independent... References

 
The Ldlr^-/-Apob^100/100 mice were far more susceptible to atherosclerosis than Apoe^-/-Apob^100/100 mice, despite virtually identical plasma cholesterol levels. How should this result be interpreted? The likely explanation is the dramatic differences in the lipoprotein phenotype, with large numbers of small lipoproteins (the phenotype in Ldlr^-/-Apob^100/100 mice) being more atherogenic than lower numbers of large lipoproteins (the phenotype in Apoe^-/-Apob^100/100 mice). In Figure 2, we plotted the total plasma cholesterol levels and atherosclerotic lesions for all 4 groups of mice, 2 of which had a preponderance of small lipoproteins (the LDL receptor–deficient mice) and 2 with a preponderance of large lipoproteins (the apo E–deficient mice). Plotted in this fashion, the data naturally suggest the possibility of a distinct "plasma cholesterol vs atherosclerosis" relationship for small and large lipoproteins. When most of the lipoproteins are in the LDL size range, increasing the plasma cholesterol levels from 200 to 300 mg/dL caused a 30-fold increase in atherosclerotic lesions. In contrast, when most of the cholesterol was in the VLDL fraction, increasing the plasma cholesterol levels from 300 to 450 mg/dL increased the extent of atherosclerosis byh2-fold.

View larger version (22K): [in this window] [in a new window]   Figure 2. Mean extent of atherosclerotic lesions plotted against the mean total plasma cholesterol level in Apoe-/-Apob100/100 (n=44), Apoe-/-Apob+/+ (n=40), Ldlr-/-Apob100/100 (n=42), and Ldlr-/-Apob+/+ (n=40) mice. Reproduced from an article by Véniant et al,8 with permission from the American Society of Clinical Investigation.

It is worthwhile emphasizing that the lipoproteins in the Apoe^-/-Apob^100/100 mice were extremely large; more than half of the cholesterol was contained in lipoproteins with diameters >70 nm. Previous studies have suggested that "giant" lipoproteins are less able to penetrate the arterial wall than are smaller lipoproteins.¹¹ Thus, the cholesterol levels within the arterial walls of Apoe^-/-Apob^100/100 mice may have been much lower than in the Ldlr^-/-Apob^100/100 mice. Lipoprotein size could also affect the propensity of lipoproteins to bind to the arterial wall matrix. Changes in particle size clearly affect the conformation of apo B-100 on the surface of lipoproteins¹²; perhaps the domains of apo B-100 that bind to the arterial wall are "hidden" in large VLDL but exposed in LDL.

Differences in lipoprotein size and number provide the most obvious explanation for the differences in atherosclerosis in Ldlr^-/-Apob^100/100 and Apoe^-/-Apob^100/100 mice, but we cannot exclude other possibilities. For example, the half-life of lipoproteins in plasma is almost certainly longer in Ldlr^-/-Apob^100/100 mice than in Apoe^-/-Apob^100/100 mice. That difference could have secondary effects on susceptibility to oxidation and thus, on the recruitment and retention of macrophages in the arterial wall. Also, we suspect that most of the lipoproteins in Ldlr^-/-Apob^100/100mice are derived from the liver and that a large percentage originate in the intestine in Apoe^-/-Apob^100/100 mice. Another difference is that the lipoproteins from Ldlr^-/-Apob^100/100 mice contain apo E, whereas those from Apoe^-/-Apob^100/100 mice do not. That compositional difference was accompanied by changes in the levels of other apolipoproteins, in both the VLDL and HDL. Perhaps those compositional differences affected lipoprotein retention within the arterial wall or the efficiency of reverse cholesterol transport. Finally, one could postulate that the absence of apo E synthesis within the arterial wall of Apoe^-/-Apob^100/100 mice was antiatherogenic or that the absence of LDL receptor expression in the arteries of Ldlr^-/-Apob^100/100 mice was proatherogenic.^8,13–15

	Implications for Studies of Atherogenesis in Mice

Top Abstract Introduction Chow-Fed Apoe-/- and Ldlr-/-... Atherosclerosis Susceptibility... Are the Differences in... Implications for Studies of... Prospects for a Diet-Independent... References

 
The Ldlr^-/-Apob^100/100 mice developed extensive atherosclerosis on a chow diet—far more than the apo E–deficient mice. Should the Ldlr^-/-Apob^100/100 mice become the preferred model for investigating atherosclerosis? Not necessarily. The choice of an animal model obviously must depend on the hypothesis to be tested. For some studies, the Ldlr^-/-Apob^100/100 mice might be ideal (eg, testing hypolipidemic or other antiatherosclerosis drugs). On the other hand, the use of these animals for genetic experiments might be inconvenient, because adding additional transgenes or knockout alleles would require onerous, time-consuming, and costly breeding.

We do, however, believe that the differences in atherosclerosis susceptibility in Ldlr^-/-Apob^100/100 and Apoe^-/-Apob^+/+ mice should heighten awareness about the potential influence of lipoprotein size and number on atherosclerosis, independent of the plasma cholesterol levels. For some types of studies, this effect might influence the interpretation of experimental results.

It is important to emphasize that "adding Apob¹⁰⁰ alleles" to Ldlr^-/- mice is not the only way to increase their LDL cholesterol levels.¹⁶ In collaboration with Powell-Braxton and Davidson, we produced Apobec1-deficient mice,¹⁷ which lack the ability to edit apo B mRNA and therefore, synthesize exclusively apo B-100. Ldlr^-/-Apobec1^-/- mice, like Ldlr^-/-Apob^100/100 mice, have high plasma apo B-100 and LDL cholesterol levels and develop severe atherosclerosis.¹⁸ The initial description of Ldlr^-/-Apobec1^-/- mice¹⁸ suggested that they might have higher plasma cholesterol levels than Ldlr^-/-Apob^100/100 mice. However, those data were obtained in mice housed in different facilities and consuming different diets. We are skeptical that those differences would hold up in side-by-side comparisons because we were unable to detect differences in the plasma apo B-100 levels of chow-fed Apob^100/100 and Apobec1^-/- mice in our facility (S. Young, unpublished data). Sanan et al¹⁹ characterized Ldlr^-/-HuBTg^+/+ mice (Ldlr-/- mice carrying a human apo B transgene²⁰). Those mice, which synthesize both apo B-48 and apo B-100, had a striking increase in plasma lipid levels and developed severe atherosclerosis.^19,21 In addition to high LDL cholesterol levels, the Ldlr^-/-HuBTg^+/+ mice had moderately high VLDL levels and high levels of triglycerides in the LDL fraction. The explanation for the hypertriglyceridemia in those animals is not clear.¹⁶

	Prospects for a Diet-Independent Model for Reversing Hypercholesterolemia

Top Abstract Introduction Chow-Fed Apoe-/- and Ldlr-/-... Atherosclerosis Susceptibility... Are the Differences in... Implications for Studies of... Prospects for a Diet-Independent... References

 
A goal of many investigators is to use mouse models to understand how hypercholesterolemia changes the biology of the arterial wall. To define how hypercholesterolemia changes arterial wall gene expression, it would be useful to have access to a hypercholesterolemic mouse model in which one could "turn off" the hypercholesterolemia and reverse the susceptibility to atherosclerosis. One could then examine the time course for atherosclerosis regression and changes in arterial wall gene expression. Such a model would be particularly valuable if the hypercholesterolemia could be reversed without changing either the diet or the nutritional status of the animal.

Microsomal triglyceride transfer protein is required for the secretion of apo B-100–containing lipoproteins from the liver.²² In a recent study, we produced mice that carried the inducible Mx1-Cre transgene²³ and were homozygous for a conditional ("floxed") allele of Mttp, the gene for microsomal triglyceride transfer protein.²⁴ After induction of the Cre transgene with a synthetic double-stranded RNA, high levels of recombination occurred in the liver, inactivating Mttp and causing apo B-100 levels to fall by >90%. Intestinal function and the nutritional status of the mice were unaffected.

We have recently bred Ldlr^-/-Apob^100/100 mice that also harbor the Mx1-Cre transgene and the floxed Mttp alleles. Preliminary studies suggest that the hypercholesterolemia in those mice can be eliminated by inducing expression of the Cre transgene. This model should be useful for studying plaque regression and for defining how hypercholesterolemia changes arterial wall gene expression.

	Acknowledgments

 
We thank S. Ordway and G. Howard for comments on the manuscript.

	Footnotes

 
This project was supported by National Institutes of Health grant HL47660 and a grant from the University of California Tobacco-Related Disease Research Program (to S.G.Y.).

Received May 23, 2001; accepted August 1, 2001.

	References

Top Abstract Introduction Chow-Fed Apoe-/- and Ldlr-/-... Atherosclerosis Susceptibility... Are the Differences in... Implications for Studies of... Prospects for a Diet-Independent... References

 

1. Piedrahita JA, Zhang SH, Hagaman JR, Oliver PM, Maeda N. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc Natl Acad Sci U S A. 1992; 89: 4471–4475.[Abstract/Free Full Text]
2. Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992; 258: 468–471.[Abstract/Free Full Text]
3. Plump AS, Smith JD, Hayek T, Aalto-Setälä K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992; 71: 343–353.[Medline] [Order article via Infotrieve]
4. Ishibashi S, Brown MS, Goldstein JL, Gerard RD, Hammer RE, Herz J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest. 1993; 92: 883–893.
5. Reddick RL, Zhang SH, Maeda N. Atherosclerosis in mice lacking apo E: evaluation of lesional development and progression. Arterioscler Thromb. 1994; 14: 141–147.[Abstract/Free Full Text]
6. Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb. 1994; 14: 133–140.[Abstract/Free Full Text]
7. Ishibashi S, Herz J, Maeda N, Goldstein JL, Brown MS. The two-receptor model of lipoprotein clearance: tests of the hypothesis in "knockout" mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proc Natl Acad Sci U S A. 1994; 91: 4431–4435.[Abstract/Free Full Text]
8. Véniant MM, Sullivan MA, Kim SK, Ambroziak P, Chu A, Wilson MD, Hellerstein MK, Rudel LL, Walzem RL, Young SG. Defining the atherogenicity of large and small lipoproteins containing apolipoprotein B100. J Clin Invest. 2000; 106: 1501–1510.[Medline] [Order article via Infotrieve]
9. Farese RV Jr, Véniant MM, Cham CM, Flynn LM, Pierotti V, Loring JF, Traber M, Ruland S, Stokowski RS, Huszar D, Young SG. Phenotypic analysis of mice expressing exclusively apolipoprotein B48 or apolipoprotein B100. Proc Natl Acad Sci U S A. 1996; 93: 6393–6398.[Abstract/Free Full Text]
10. Véniant MM, Zlot CH, Walzem RL, Pierotti V, Driscoll R, Dichek D, Herz J, Young SG. Lipoprotein clearance mechanisms in LDL receptor-deficient "apo-B48-only" and "apoB100-only" mice. J Clin Invest. 1998; 102: 1559–1568.[Medline] [Order article via Infotrieve]
11. Nordestgaard BG, Zilversmit DB. Large lipoproteins are excluded from the arterial wall in diabetic cholesterol-fed rabbits. J Lipid Res. 1988; 29: 1491–1500.[Abstract]
12. Tsao BP, Curtiss LK, Edgington TS. Immunochemical heterogeneity of human plasma apolipoprotein B, II: expression of apolipoprotein B epitopes on native lipoproteins. J Biol Chem. 1982; 257: 15222–15228.[Abstract/Free Full Text]
13. Linton MF, Babaev VR, Gleaves LA, Fazio S. A direct role for the macrophage low density lipoprotein receptor in atherosclerotic lesion formation. J Biol Chem. 1999; 274: 19204–19210.[Abstract/Free Full Text]
14. Fazio S, Babaev VR, Murray AB, Hasty AH, Carter KJ, Gleaves LA, Atkinson JB, Linton MF. Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages. Proc Natl Acad Sci U S A. 1997; 94: 4647–4652.[Abstract/Free Full Text]
15. Boisvert WA, Curtiss LK. Elimination of macrophage-specific apolipoprotein E reduces diet-induced atherosclerosis in C57BL/6J male mice. J Lipid Res. 1999; 40: 806–813.[Abstract/Free Full Text]
16. Kim E, Young SG. Genetically modified mice for the study of apolipoprotein B. J Lipid Res. 1998; 39: 703–723.[Abstract/Free Full Text]
17. Hirano K-I, Young SG, Farese RV Jr, Ng J, Sande E, Warburton C, Powell-Braxton LM, Davidson NO. Targeted disruption of the mouse apobec-1 gene abolishes apolipoprotein B mRNA editing and eliminates apolipoprotein B48. J Biol Chem. 1996; 271: 9887–9890.[Abstract/Free Full Text]
18. Powell-Braxton L, Véniant M, Latvala RD, Hirano K-I, Won WB, Ross J, Dybdal N, Zlot CH, Young SG, Davidson NO. A mouse model of human familial hypercholesterolemia: markedly elevated low density lipoprotein cholesterol levels and severe atherosclerosis on a low-fat chow diet. Nat Med. 1998; 4: 934–938.[Medline] [Order article via Infotrieve]
19. Sanan DA, Newland DL, Tao R, Marcovina S, Wang J, Mooser V, Hammer RE, Hobbs HH. Low density lipoprotein receptor-negative mice expressing apolipoprotein B-100 develop complex atherosclerotic lesions on a chow diet: no accentuation by apolipoprotein(a). Proc Natl Acad Sci U S A. 1998; 95: 4544–4549.[Abstract/Free Full Text]
20. Linton MF, Farese RV Jr, Chiesa G, Grass DS, Chin P, Hammer RE, Hobbs HH, Young SG. Transgenic mice expressing high plasma concentrations of human apolipoprotein B100 and lipoprotein(a). J Clin Invest. 1993; 92: 3029–3037.
21. Rudel LL, Kelley K, Sawyer JK, Shah R, Wilson MD. Dietary monounsaturated fatty acids promote aortic atherosclerosis in LDL receptor-null, human apoB100-overexpressing transgenic mice. Arterioscler Thromb Vasc Biol. 1998; 18: 1818–1827.[Abstract/Free Full Text]
22. Wetterau JR, Aggerbeck LP, Bouma M-E, Eisenberg C, Munck A, Hermier M, Schmitz J, Gay G, Rader DJ, Gregg RE. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science. 1992; 258: 999–1001.[Abstract/Free Full Text]
23. Gu H, Marth JD, Orban PC, Mossmann H, Rajewsky K. Deletion of a DNA polymerase ß gene segment in T cells using cell type-specific gene targeting. Science. 1994; 265: 103–106.[Abstract/Free Full Text]
24. Raabe M, Véniant MM, Sullivan MA, Zlot CH, Björkegren J, Nielsen LB, Wong JS, Hamilton RL, Young SG. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice. J Clin Invest. 1999; 103: 1287–1298.[Medline] [Order article via Infotrieve]

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				I. Shai, E. B. Rimm, S. E. Hankinson, G. Curhan, J. E. Manson, N. Rifai, M. J. Stampfer, and J. Ma Multivariate Assessment of Lipid Parameters as Predictors of Coronary Heart Disease Among Postmenopausal Women: Potential Implications for Clinical Guidelines Circulation, November 2, 2004; 110(18): 2824 - 2830. [Abstract] [Full Text] [PDF]

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				M. Kratz, E. Gulbahce, A. von Eckardstein, P. Cullen, A. Cignarella, G. Assmann, and U. Wahrburg Dietary Mono- and Polyunsaturated Fatty Acids Similarly Affect LDL Size in Healthy Men and Women J. Nutr., April 1, 2002; 132(4): 715 - 718. [Abstract] [Full Text] [PDF]

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