TY - JOUR
T1 - 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
AU - Greeve, Jobst
AU - Jona, Vinod K.
AU - Roy Chowdhury, Namita
AU - Horwitz, Marshall S.
AU - Roy Chowdhury, Jayanta
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 1996/9
Y1 - 1996/9
N2 - 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.
AB - 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.
KW - adenovirus-mediated gene transfer
KW - apoB mRNA editing
KW - apoB mRNA editing catalytic polypeptide-1
KW - atherosclerosis
UR - http://www.scopus.com/inward/record.url?scp=0029794714&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029794714&partnerID=8YFLogxK
M3 - Article
C2 - 8895066
AN - SCOPUS:0029794714
SN - 0022-2275
VL - 37
SP - 2001
EP - 2017
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 9
ER -