TYPE-III HYPERLIPOPROTEINEMIC PHENOTYPE IN TRANSGENIC MICE EXPRESSING DYSFUNCTIONAL APOLIPOPROTEIN-E

被引:71
作者
FAZIO, S
LEE, YL
JI, ZS
RALL, SC
机构
[1] Gladstone Inst. of Cardiovasc. Dis., Cardiovascular Research Institute, University of California, San Francisco
[2] Gladstone Inst. of Cardiovasc. Dis., San Francisco, CA 94141-9100
关键词
APOLIPOPROTEIN-E; CHOLESTEROL; HYPERLIPIDEMIA; TRANSGENIC MICE; BETA-VERY LOW DENSITY LIPOPROTEINS;
D O I
10.1172/JCI116728
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Transgenic mice were prepared that expressed a dysfunctional apo E variant, apo E(Arg-112, Cys-142), which is associated with dominant inheritance of type III hyperlipoproteinemia (type III HLP) in humans. Among eight founder mice, plasma apo E(Arg-112, Cys-142) levels varied 100-fold and directly correlated with plasma cholesterol and triglyceride levels. On a normal chow diet, mice expressing high levels (> 70 mg/dl) of the dysfunctional apo E had grossly elevated plasma lipids, with cholesterol levels of up to 410 mg/dl and triglyceride levels of up to 1,210 mg/dl. Upon agarose electrophoresis, plasma from these mice demonstrated beta-very low density lipoproteins (beta-VLDL). Mice expressing low (< 2.5 mg/dl) or intermediate (21 mg/dl) levels of the apo E variant had much less severe hyperlipidemia and did not have beta-VLDL. Although the transgenic mouse beta-VLDL were enriched in cholesteryl esters compared with normal mouse VLDL, they were not as cholesterol enriched as human beta-VLDL from type III HLP subjects. Transgenic mouse beta-VLDL injected into normal mice were cleared from plasma at a significantly slower rate than normal mouse VLDL demonstrating the impaired catabolism of beta-VLDL. Thus, transgenic mice expressing high levels of the dysfunctional apo E(Arg-112, Cys-142) variant have many characteristics of the human type Ill HLP phenotype and appear to be a suitable animal model for this disorder.
引用
收藏
页码:1497 / 1503
页数:7
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