Adenovirus-mediated gene transfer of rat apolipoprotein B mRNA-editing protein in mice virtually eliminates apolipoprotein B-100 and normal low density lipoprotein production

B. Teng, S. Blumenthal, T. Forte, N. Navaratnam, J. Scott, A. M. Gotto, L. Chan

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

Abstract

Apolipoprotein (apo) B-100 is the major protein component in low density lipoprotein (LDL); it contains the binding domain for the LDL receptor and the attachment site for apolipoprotein(a) in lipoprotein(a). ApoB-48 is colinear with the amino-terminal half of apoB-100 and misses the part of the molecule required for LDL receptor interaction and lipoprotein(a) formation. ApoB-48 mRNA is produced by the editing of apoB-100 mRNA, a process by which the codon CAA for Gln-2153 is changed to UAA, an in-frame stop codon. We used the cloned catalytic component of the rat apoB mRNA-editing enzyme (REPR) to construct a replication-defective recombinant adenoviral vector containing REPR cDNA (AvREPR) and a control vector (Av1LacZ4) containing a β-galactosidase cDNA to investigate the effect of REPR gene delivery in C57BL/6 mice. Intravenous injection of AvREPR in mice resulted in efficient transduction of liver cells, where REPR mRNA and protein were overexpressed, reaching a peak at 7 and 12 days, returning toward control levels at 39 days after AvREPR administration. ApoB mRNA editing activity in liver extracts showed changes parallel to those of REPR mRNA expression; the proportion of edited apoB mRNA in the total hepatic apoB mRNA increased from ∼60% to more than 90% at the peak of REPR expression. The proportion of plasma apoB-100 in AvREPR-transduced animals decreased from ∼50% to <10% of total plasma apoB concentration. Plasma very low density lipoproteins were polydisperse in control animals with an average diameter of 54.9 ± 20.6 nm (uninjected control) and 54.7 ± 16.8 nm (Av1LacZ4-treated), respectively. They became much smaller (average diameter 39.3 ± 12.7 nm) and more uniform in size at day 12 following AvREPR administration. On the same day, the normal plasma LDL (26.2-25.5 nm) was almost completely eliminated in treated animals. Adenovirus-mediated transfer of the REPR cDNA is an efficient method to reduce plasma apoB-100 and normal LDL production.

Original languageEnglish (US)
Pages (from-to)29395-29405
Number of pages11
JournalJournal of Biological Chemistry
Volume269
Issue number47
StatePublished - 1994

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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