Effective lowering of plasma, LDL, and esterified cholesterol in LDL receptor-knockout mice by adenovirus-mediated gene delivery of ApoB mRNA editing enzyme (Apobec1)

Babie Teng, Brian Ishida, Trudy M. Forte, Scott Blumenthal, Li Zhen Song, Antonio Gotto, Lawrence Chan

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Adenovirus-mediated gene delivery of apolipoprotein (apo)B mRNA editing enzyme (AvApobec1) was used to study the effect of apoB mRNA editing on apoB production in homozygous LDL receptor-deficient (LDLR-/-) mice. Intravenous injection of AvApobec1 into these mice resulted in a >80% decrease in plasma apoB-100 with a concomitant increase in plasma apoB-48 level. The plasma apoE level also increased. In all cases, total plasma apoB (apoB-100 + apoB-48) decreased by 60% at day 5 and remained ≃40% lower in AvApobec1-treated compared with control vector Av1LacZA-treated animals at day 12. On day 12, total plasma cholesterol decreased by 29% in male mice and 18% in female mice that were transduced with AvApobec1. This was reflected in a reduction in apoB-containing lipoprotein cholesterol, which decreased by 34% and 27% in male and female mice, respectively. Apobec1 gene transfer also decreased the cholesteryl ester contents in the LDL fraction, which were 16%, 22%, and 22% in female and 20%, 20%, and 15% in male animals on days 5, 7, and 12, respectively, compared with Av1LacZ controls with 29%, 32%, and 33%, respectively, in female and 29%, 38%, and 36%, respectively, in male animals. Nondenaturing gradient gel electrophoresis indicated almost complete elimination of LDL particles of 29, 27, and 25 nm at days 7 and 12. We conclude that in the absence of a functioning LDL receptor, hepatic overexpression of Apobec1 is highly efficient in lowering plasma apoB-100 levels, leading to the almost complete elimination of LDL particles and a reduction in LDL cholesterol and cholesteryl ester content.

Original languageEnglish (US)
Pages (from-to)889-897
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume17
Issue number5
DOIs
StatePublished - 1997

Keywords

  • apoB mRNA editing
  • gene therapy
  • hypercholesterolemia
  • LDL receptor-deficient mouse
  • lipoproteins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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