Effective lowering of plasma, LDL, and esterified cholesterol in LDL receptor-knockout mice by adenovirus-mediated gene delivery of ApoB mRNA editing enzyme (Apobec1).
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 approximately 40% lower in AvApobec1-treated compared with control vector Av1LacZ4-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.
Teng
B
B
Department of Medicine, Baylor College of Medicine, Houston, Tex 77030, USA. teng@bcm.tmc.edu
Ishida
B
B
Forte
T M
TM
Blumenthal
S
S
Song
L Z
LZ
Gotto
A M
AM
Chan
L
L
D000071479:APOBEC-1 Deaminase; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001055:Apolipoproteins B / Q000235:genetics*; D001057:Apolipoproteins E / Q000097:blood; D002784:Cholesterol / Q000097:blood*; D002788:Cholesterol Esters / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood*; D003564:Cytidine Deaminase / Q000235:genetics*; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D002788:Cholesterol Esters; D008078:Cholesterol, LDL; D012333:RNA, Messenger; D011973:Receptors, LDL; D002784:Cholesterol; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000071479:APOBEC-1 Deaminase; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase