HEPATIC EXPRESSION OF THE CATALYTIC SUBUNIT OF THE APOLIPOPROTEIN-B MESSENGER-RNA EDITING ENZYME (APOBEC-1) AMELIORATES HYPERCHOLESTEROLEMIA IN LDL RECEPTOR-DEFICIENT RABBITS

Apolipoprotein (ape) B48, a protein contained in intestinally derived lipoprotein particles, is synthesized by post-transcriptional editing of apoB100 mRNA, This reaction is mediated by an enzyme complex that i ncludes the catalytic subunit, apobec-1, The liver of most mammals, by contrast, contains only unedited apoB mRNA and secretes apoB100, the major protein component of plasma low-density lipoprotein (LDL). Becau se rabbits, like humans, fail to edit hepatic apoB100 mRNA, we introdu ced a recombinant adenovirus encoding apobec-1 into the livers of LDL receptor-defective rabbits to determine the impact on lipoprotein meta bolism of hepatic apoB48 secretion, Transgene expression was mainly co nfined to the liver and was sustained for up to 3 weeks following viru s administration, as evidenced by the presence of apobec-1 mRNA and th e ability of hepatic S100 extracts to edit a synthetic apoB RNA templa te in vitro, The transient induction of hepatic apoB mRNA editing acco mpanied alterations in very-low-density lipoprotein (VLDL) size, the p resence of apoB48 in fractions spanning the VLDL and LDL range, and mo dest reductions in total plasma cholesterol levels.