HYPERCHOLESTEROLEMIA IN LOW-DENSITY-LIPOPROTEIN RECEPTOR KNOCKOUT MICE AND ITS REVERSAL BY ADENOVIRUS-MEDIATED GENE DELIVERY
HYPERCHOLESTEROLEMIA IN LOW-DENSITY-LIPOPROTEIN RECEPTOR KNOCKOUT MICE AND ITS REVERSAL BY ADENOVIRUS-MEDIATED GENE DELIVERY
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DOI：
10.1172/jci116663
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发表时间：
1993-08-01
影响因子：
15.9
通讯作者：
HERZ, J
中科院分区：
文献类型：
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作者：
ISHIBASHI, S;BROWN, MS;HERZ, J
我们利用胚胎干细胞的同源重组来产生缺乏功能性LDL受体基因的小鼠。缺乏LDL受体的纯合子雄性和雌性小鼠（LDLR-/-小鼠）存活且可生育。血浆总胆固醇水平比野生型同窝仔高两倍，这是由于中密度脂蛋白（IDL）和LDL增加了7至9倍，而HDL没有显著变化。血浆甘油三酯水平正常。静脉注射I-125-VLDL和I-125-LDL的半衰期分别延长了30倍和2.5倍，但在LDLR-/-小鼠中I-125-HDL的清除率正常。与野生型小鼠不同，LDLR-/-小鼠对适量的膳食胆固醇（0.2%胆固醇/10%椰子油）有反应，IDL和LDL颗粒的胆固醇含量显著增加。静脉注射由巨细胞病毒启动子驱动的编码人LDL受体的重组复制缺陷型腺病毒后，LDLR-/-小鼠升高的IDL/LDL水平降至正常4 d。该病毒恢复了肝脏中LDL受体蛋白的表达，并增加了I-125-VLDL的清除率。我们的结论是，LDL受体是负责部分低水平的极低密度脂蛋白，IDL和LDL在野生型小鼠和腺病毒编码的LDL受体可以急性逆转LDL受体缺乏症的高胆固醇血症的影响。
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.