HYPERCHOLESTEROLEMIA IN LOW-DENSITY-LIPOPROTEIN RECEPTOR KNOCKOUT MICE AND ITS REVERSAL BY ADENOVIRUS-MEDIATED GENE DELIVERY

被引:1312
作者
ISHIBASHI, S
BROWN, MS
GOLDSTEIN, JL
GERARD, RD
HAMMER, RE
HERZ, J
机构
[1] UNIV TEXAS, SW MED CTR, DEPT BIOCHEM, DALLAS, TX 75235 USA
[2] UNIV TEXAS, SW MED CTR, HOWARD HUGHES MED INST, DALLAS, TX 75235 USA
关键词
HOMOLOGOUS RECOMBINATION; LIPOPROTEIN METABOLISM; VERY LOW DENSITY LIPOPROTEIN; GENE THERAPY; LIVER RECEPTORS;
D O I
10.1172/JCI116663
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
We employed homologous recombination in embryonic stem cells to produce mice lacking functional LDL receptor genes. Homozygous male and female mice lacking LDL receptors (LDLR-/- mice) were viable and fertile. Total plasma cholesterol levels were twofold higher than those of wild-type litter-mates, owing to a seven- to ninefold increase in intermediate density lipoproteins (IDL) and LDL without a significant change in HDL. Plasma triglyceride levels were normal. The half-lives for intravenously administered I-125-VLDL and I-125-LDL were prolonged by 30-fold and 2.5-fold, respectively, but the clearance of I-125-HDL was normal in the LDLR-/- mice. Unlike wild-type mice, LDLR-/- mice responded to moderate amounts of dietary cholesterol (0.2% cholesterol/10% coconut oil) with a major increase in the cholesterol content of IDL and LDL particles. The elevated IDL/LDL level of LDLR-/- mice was reduced to normal 4 d after the intravenous injection of a recombinant replication-defective adenovirus encoding the human LDL receptor driven by the cytomegalovirus promoter. The virus restored expression of LDL receptor protein in the liver and increased the clearance of I-125-VLDL. We conclude that the LDL receptor is responsible in part for the low levels of VLDL, IDL, and LDL in wild-type mice and that adenovirus-encoded LDL receptors can acutely reverse the hypercholesterolemic effects of LDL receptor deficiency.
引用
收藏
页码:883 / 893
页数:11
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