Apo E structure determines VLDL clearance and atherosclerosis risk in mice
Christopher Knouff, … , Patrick M. Sullivan, Nobuyo Maeda
Christopher Knouff, … , Patrick M. Sullivan, Nobuyo Maeda
Published June 1, 1999
Citation Information: J Clin Invest. 1999;103(11):1579-1586. https://doi.org/10.1172/JCI6172.
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Article

Apo E structure determines VLDL clearance and atherosclerosis risk in mice

Abstract

We have generated mice expressing the human apo E4 isoform in place of the endogenous murine apo E protein and have compared them with mice expressing the human apo E3 isoform. Plasma lipid and apolipoprotein levels in the mice expressing only the apo E4 isoform (4/4) did not differ significantly from those in mice with the apo E3 isoform (3/3) on chow and were equally elevated in response to increased lipid and cholesterol in their diet. However, on all diets tested, the 4/4 mice had approximately twice the amount of cholesterol, apo E, and apo B-48 in their VLDL as did 3/3 mice. The 4/4 VLDL competed with human LDL for binding to the human LDL receptor slightly better than 3/3 VLDL, but the VLDL clearance rate in 4/4 mice was half that in 3/3 mice. On an atherogenic diet, there was a trend toward greater atherosclerotic plaque size in 4/4 mice compared with 3/3 mice. These data, together with our earlier observations in wild-type and human APOE*2-replacement mice, demonstrate a direct and highly significant correlation between VLDL clearance rate and mean atherosclerotic plaque size. Therefore, differences solely in apo E protein structure are sufficient to cause alterations in VLDL residence time and atherosclerosis risk in mice.

Authors

Christopher Knouff, Myron E. Hinsdale, Hafid Mezdour, Michael K. Altenburg, Masahiko Watanabe, Steven H. Quarfordt, Patrick M. Sullivan, Nobuyo Maeda

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Figure 1

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(a) Mice with the 3 human apo E isoforms. Delipidated plasma samples fro...
(a) Mice with the 3 human apo E isoforms. Delipidated plasma samples from 2/2 (lane 2), 3/3 (lane 3), and 4/4 (lane 4) mice were separated by isoelectric focusing, and the apo E proteins were viewed by silver staining after immunofixation with an anti-human apo E antibody. The positions of the human apo E isoforms — E2, E3, and E4 — are indicated. Lane 1 shows apo E2, apo E3, and apo E4 from mixed human plasma as controls. (b) Competition assay of human LDL receptor binding and internalization of VLDL from 2/2, 3/3, and 4/4 mice. VLDL was isolated from 2/2 (filled squares), 3/3 (filled circles), and 4/4 (open triangles) mice maintained on an HFC diet by ultracentrifugation of plasma pooled from at least 6 animals, and it was used to compete with DiIC18-labeled human LDL for binding to human fibroblasts. Values are the mean ± SD of 4 wells from a representative experiment carried out at 37°C. VLDL amounts are expressed as micrograms of total protein. The apo E content of the isolated VLDL was approximately 17 ± 3%, 7 ± 3%, and 4 ± 1% of total protein for 2/2, 3/3, and 4/4 VLDL, respectively (P < 0.001 by one-way ANOVA).