Hepatic gene transfer of the catalytic subunit of the apolipoprotein B mRNA editing enzyme results in a reduction of plasma LDL levels in normal and Watanabe heritable hyperlipidemic rabbits

Jobst Greeve, Vinod K. Jona, Namita Roy Chowdhury, Marshall S. Horwitz, Jayanta Roy Chowdhury

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Apolipoprotein (apo) B exists in two forms, the full length protein apoB-100 and the carboxyterminal-truncated apoB48 that is synthesized in the intestine due to editing of the apoB mRNA which generates a premature stop codon. To determine whether gene transfer of the catalytic subunit of the apoB mRNA editing enzyme APOBEC- 1 (apoB mRNA editing enzyme catalytic polypeptide 1) into the liver of rabbits reconstitutes hepatic apoB mRNA editing and how this affects the plasma levels of apoB-containing lipoproteins, we constructed all APOBEC-1 recombinant adenovirus (Ad APOBEC- 1). After injection of Ad APOBEC-1 into normal New Zealand White (NZW) or Watanabe heritable hyperlipidemic (WHHL) rabbits, up to 50% of the hepatic apoB, mRNA was edited and freshly isolated hepatocytes secreted predominantly apoB-48-containing lipoproteins. VLDL isolated from Ad APOBEC-1-treated NZW and WHHL rabbits contained both apoB-100 and apoB-48, whereas that from control rabbits infected with a β-galactosidase recombinant adenovirus (Ad LacZ) contained exclusively apoB-100. VLDL from WHHL rabbits treated with Ad APOBEC-1 had the same particle size, lipid composition, and content of apolipoprotein E as VLDL, from Ad LacZ-infected control animals. An increase of VLDL, was observed in NZW and WHHL rabbits after infection with Ad APOBEC- I as well as Ad LacZ. After injection of Ad APOBEC-1, LDL became undetectable in the plasma of NZW rabbits and was reduced by an average of 65% in the plasma of WHHL rabbits compared to Ad LacZ-infected controls. LDL from Ad APOBEC-1-infected WHHL rabbits contained only apoB-100. VLDL isolated from Ad APOBEC-1-infected WHHL rabbits were rapidly cleared from the circulation after injection into NZW rabbits. These results provide further evidence that the switch in the hepatic synthesis from exclusively apoB-100 to partly apoB- 48 can result in a reduction of LDL formation that requires the full-length apoB-100.

Original languageEnglish (US)
Pages (from-to)2001-2017
Number of pages17
JournalJournal of Lipid Research
Volume37
Issue number9
StatePublished - Sep 1 1996

Keywords

  • adenovirus-mediated gene transfer
  • apoB mRNA editing
  • apoB mRNA editing catalytic polypeptide-1
  • atherosclerosis

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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