TARGETED DISRUPTION OF THE MOUSE APOBEC-1 GENE ABOLISHES APOLIPOPROTEIN-B MESSENGER-RNA EDITING AND ELIMINATES APOLIPOPROTEIN B48

A site-specific C to U editing reaction modifies nuclear apolipoprotei n B100 (apoB100) mRNA, producing apolipoprotein B48 in the mammalian s mall intestine, This reaction is mediated by a multicomponent enzyme c omplex, which contains a catalytic subunit, Apobec-1. We have used gen e targeting to disrupt mouse apobec-1 in order to establish its requis ite importance in apoB mRNA editing and also, in view of its widesprea d tissue distribution in rodents, as a preliminary indication of other potential roles. Both heterozygous (apobec-1(+/-)) and homozygous (ap obec-1(-/-)) gene-targeted mice appear healthy and fertile with no alt erations in serum cholesterol or triglyceride concentrations. The apob ec-1(+/-) mice demonstrated reduced levels of hepatic apoB mRNA editin g. By contrast, levels of small intestinal apoB mRNA editing were indi stinguishable in wild-type and apobec-1(+/-) animals, suggesting that Apobec-1 is expressed in limited quantities in the liver but not in th e small intestine. The apobec-1(-/-) mice lacked detectable levels of Apobec-1 mRNA, expressed only unedited apoB mRNA in all tissues, and c ontained no apoB48 in their serum, demonstrating that there is no func tional duplication of this gene.