REPR AND COMPLEMENTATION FACTOR(S) INTERACT TO MODULATE RAT APOLIPOPROTEIN-B MESSENGER-RNA EDITING IN RESPONSE TO ALTERATIONS IN CELLULAR CHOLESTEROL FLUX

Apolipoprotein B (apoB) mRNA editing is a post-transcriptional cytidin e deamination involving several protein factor(s), one of which has re cently been cloned. We have examined the effects of alterations in cel lular cholesterol flux in the rat liver and small intestine as a means of dissecting the physiologic mechanisms regulating apoB mRNA editing , both in vivo and in isolated S-100 extracts. Hepatic cholesteryl est er accumulation was produced by feeding rats a high cholesterol diet, alone, or in combination with either ethinyl estradiol treatment, or a fter induction of hypothyroidism. Endogenous hepatic apoB mRNA editing decreased in parallel with the increase in cellular cholesteryl ester content (r = -0.948, P < 0.001). None of these conditions altered end ogenous intestinal apoB mRNA editing. Hepatic S-100 extracts demonstra ted decreased in vitro apoB RNA editing activity, in parallel with the changes observed in vivo. By contrast, the activity of intestinal S-1 00 extracts demonstrated a paradoxical increase in hypothyroid rats an d a similar, paradoxical decrease in hyperthyroid rats, when compared to controls. Hepatic REPR mRNA, quantitated by RNase protection assay, showed a 25-50% decrease in cholesterol-fed rats. The editing activit y of hepatic S-100 extracts prepared from cholesterol-fed, hypothyroid rats was restored to control levels with REPR supplementation but not with chicken intestinal S-100 extracts, suggesting that changes in RE PR, but not complementation activity, may play a critical role in the regulation of apoB mRNA editing in rat liver. By contrast, the editing activity of intestinal S-100 extracts prepared from hyperthyroid anim als was unaltered by supplementation with REPR, but was restored to co ntrol levels after the addition of chicken intestinal S-100 extracts. jlr Taken together, the data suggest that tissue-specific factors regu late apoB mRNA editing in the rat and that the complex interplay of RE PR and complementation factor(s) may be modulated in response to alter ations in cholesterol flux, in vivo.