Type III hyperlipoproteinemic phenotype in transgenic mice expressing dysfunctional apolipoprotein E.
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 III HLP phenotype and appear to be a suitable animal model for this disorder.
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco 94141-9100.
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Fazio
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Lee
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Ji
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Rall
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006952:Hyperlipoproteinemia Type III / Q000235:genetics*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics
D001057:Apolipoproteins E; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger