EFFECTIVE LOWERING OF PLASMA, LDL, AND ESTERIFIED CHOLESTEROL IN LDL RECEPTOR KNOCKOUT MICE BY ADENOVIRUS-MEDIATED GENE DELIVERY OF APO-B MESSENGER-RNA EDITING ENZYME (APOBEC1)
Bb. Teng et al., EFFECTIVE LOWERING OF PLASMA, LDL, AND ESTERIFIED CHOLESTEROL IN LDL RECEPTOR KNOCKOUT MICE BY ADENOVIRUS-MEDIATED GENE DELIVERY OF APO-B MESSENGER-RNA EDITING ENZYME (APOBEC1), Arteriosclerosis, thrombosis, and vascular biology, 17(5), 1997, pp. 889-897
Adenovirus-mediated gene delivery of apolipoprotein (apo)B mRNA editin
g enzyme (AvApobec1) was used to study the effect of apoB mRNA editing
on apoB production in homozygous LDL receptor-deficient (LDLR-/-) mic
e. Intravenous injection of AvApobec1 into these mice resulted in a >8
0% decrease in plasma apoB-100 with a concomitant increase in plasma a
poB-48 level. The plasma apoE level also increased. In all cases, tota
l plasma apoB (apoB-100 + apoB-48) decreased by 60% at day 5 and remai
ned approximate to 40% lower in AvApobec1-treated compared with contro
l vector Av1LacZ4-treated animals at day 12. On day 12, total plasma c
holesterol decreased by 29% in male mice and 18% in female mice that w
ere transduced with AvApobec1. This was reflected in a reduction in ap
oB-containing lipoprotein cholesterol, which decreased by 34% and 27%
in male and female mice, respectively. Apobec1 gene transfer also decr
eased the cholesteryl eater contents in the LDL fraction, which were 1
6%, 22%, and 22% in female and 20%, 20%, and 15% in male animals on da
ys 5, 7, and 12, respectively, compared with Av1LacZ controls with 29%
, 32%, and 33%, respectively, in female and 29%, 38%, and 36%, respect
ively, in male animals. Nondenaturing gradient gel electrophoresis ind
icated 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 elimi
nation of LDL particles and a reduction in LDL cholesterol and cholest
eryl ester content.