Transgenic mice expressing full-length human apolipoprotein B-100: Full-length human apolipoprotein B mRNA is essentially not edited in mouse intestine or liver

Apolipoprotein (apo) B-100 mRNA is edited in the small intestine (in all mammals examined) and the liver (in mice and rats only) to produce apoB-48 mRNA. ApoB mRNA editing involves a C → U conversion of the first base of the codon CAA for Gln-2153 in apoB-100, changing it to an in-frame stop codon (UAA). The edited mRNA encodes apoB-48, which is colinear with the N-terminal 48% of apoB-100. ApoB mRNA editing can be reproduced in vitro using cellular extracts from one species to edit synthetic apoB mRNA sequences from a different species. Editing of transcripts from transfected genes also appears not to be species-specific. We have produced transgenic mice that express full-length human apoB-100 mRNA at high levels in the liver and small intestine. Human apoB-100 (a 550-kDa protein) but not apoB-48 (a 260-kDa protein) is detected in total plasma (at ∼22 mg/dl) and in very low density and low density lipoproteins. The endogenous mouse plasma apoB concentration is reduced by ∼45% in the transgenic animals. Thus, the transgenic mice form an animal model for familial hyperapolipoprotein B, an inherited form of hyperlipidemia. To our surprise, we found that the full-length human apoB mRNA consists of >99% apoB-100 mRNA in both the liver and small intestine; <1% of edited (apoB-48) mRNA was detected. The proportions of endogenous mouse apoB-48 (edited) mRNA (60 and 90% in the liver and small intestine, respectively) were identical in transgenic mice and their nontransgenic littermates. Therefore, full-length human apoB mRNA is resistant to editing by the mouse editing enzyme in vivo; the unchanged proportion of endogenous mouse apoB-48 mRNA in the transgenic mice suggests that the human mRNA competes poorly with the mouse sequence for interacting with the editing enzyme. This observation has implications for the sequence specificity and mechanism of RNA editing. Furthermore, we should exercise caution in the interpretation of in vitro RNA-editing experiments.