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.
Apolipoprotein (apo) B exists in two forms, the full length protein apoB-100 and the carboxyterminal-truncated apoB-48 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 an 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 beta-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-1 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.
Medizinische Klinik, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany.
J
J
Greeve
V K
VK
Jona
N R
NR
Chowdhury
M S
MS
Horwitz
J R
JR
Chowdhury
D000071479:APOBEC-1 Deaminase; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D003564:Cytidine Deaminase / Q000235:genetics*; D005215:Fasting; D018014:Gene Transfer Techniques; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000097:blood* / Q000737:chemistry; D008079:Lipoproteins, VLDL / Q000737:chemistry / Q000648:ultrastructure; D008099:Liver / Q000378:metabolism*; D008297:Male; D017393:RNA Editing; D011817:Rabbits; D051381:Rats; D014280:Triglycerides / Q000097:blood; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000071479:APOBEC-1 Deaminase; C000605091:Apobec1 protein, rat; D003564:Cytidine Deaminase