Hepatic Expression of the Catalytic Subunit of the Apolipoprotein B mRNA Editing Enzyme (apobec-1) Ameliorates Hypercholesterolemia in LDL Receptor-Deficient Rabbits

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Abstract
Apolipoprotein (apo) 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 includes 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). Because rabbits, like humans, fail to edit hepatic apoB100 mRNA, we introduced a recombinant adenovirus encoding apobec-1 into the livers of LDL receptor-defective rabbits to determine the impact on lipoprotein metabolism of hepatic apoB48 secretion. Transgene expression was mainly confined to the liver and was sustained for up to 3 weeks following virus administration, as evidenced by the presence of apobec-1 mRNA and the ability of hepatic S100 extracts to edit a synthetic apoB RNA template in vitro. The transient induction of hepatic apoB mRNA editing accompanied alterations in very-low-density lipoprotein (VLDL) size, the presence of apoB48 in fractions spanning the VLDL and LDL range, and modest reductions in total plasma cholesterol levels. Recombinant adenovirus is a useful tool not only for gene therapy, but also for elucidating in vivo functions of recently cloned genes. apobec-1 is the catalytic subunit of the enzyme complex responsible for synthesis of apoB48 mRNA by post-transcriptional editing of the apolipoprotein B100 (apoB100) mRNA. In rabbits and humans, unlike mice, the liver normally produces only apoB100 mRNA. A recombinant adenovirus encoding apobec-1 was generated to determine whether apobec-1 expression in rabbit liver would be sufficient to produce hepatic apoB48, and the effects of lipoprotein levels in a rabbit model of human familial hypercholesterolemia. The resulting expression of apoB48, accompanied by moderate decreases in plasma cholesterol, confirm that hepatic apobec-1 expression confers the ability to edit apoB100 mRNA, and alters lipoprotein profiles in hypercholesterolemic animals.