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 journalArticlepeer-review

1170 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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