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

Shun Ishibashi, Michael S Brown, Joseph L Goldstein, Robert D. Gerard, Robert E Hammer, Joachim Herz

Research output: Contribution to journalArticle

1150 Scopus citations

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 adenovirusencoded LDL receptors can acutely reverse the hypercholesterolemic effects of LDL receptor deficiency.

Original languageEnglish (US)
Pages (from-to)883-893
Number of pages11
JournalJournal of Clinical Investigation
Volume92
Issue number2
DOIs
StatePublished - Aug 1993

Keywords

  • Gene therapy
  • Homologous recombination
  • Lipoprotein metabolism
  • Liver receptors
  • Very low density lipoprotein

ASJC Scopus subject areas

  • Medicine(all)

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