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      Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery.

      The Journal of clinical investigation

      Alleles, Animals, Base Sequence, Cholesterol, blood, Cholesterol, Dietary, Chromosome Mapping, Crosses, Genetic, Embryo, Mammalian, Female, Genetic Therapy, Humans, Hypercholesterolemia, genetics, metabolism, therapy, Lipoproteins, Lipoproteins, IDL, Lipoproteins, LDL, Lipoproteins, VLDL, Liver, Male, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Oligodeoxyribonucleotides, Receptors, LDL, analysis, Recombination, Genetic, Restriction Mapping, Stem Cells

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          Abstract

          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 125I-VLDL and 125I-LDL were prolonged by 30-fold and 2.5-fold, respectively, but the clearance of 125I-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 125I-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.

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          Author and article information

          Journal
          10.1172/JCI116663
          294927
          8349823

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