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Research Article Free access | 10.1172/JCI2673

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

P M Sullivan, H Mezdour, S H Quarfordt, and N Maeda

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7525, USA.

Find articles by Sullivan, P. in: PubMed | Google Scholar

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7525, USA.

Find articles by Mezdour, H. in: PubMed | Google Scholar

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7525, USA.

Find articles by Quarfordt, S. in: PubMed | Google Scholar

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7525, USA.

Find articles by Maeda, N. in: PubMed | Google Scholar

Published July 1, 1998 - More info

Published in Volume 102, Issue 1 on July 1, 1998
J Clin Invest. 1998;102(1):130–135. https://doi.org/10.1172/JCI2673.
© 1998 The American Society for Clinical Investigation
Published July 1, 1998 - Version history
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Abstract

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

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