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)

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.