Ethanol modulates apolipoprotein B mRNA editing in the rat.

We have studied the rat ethanol-liquid diet model for chronic ethanol modulation of lipid homeostasis, apolipoprotein (apo) B production and apoB mRNA editing. Male Wistar rats were fed one of three diets: i) regular chow, ii) an isocaloric liquid diet, or iii) isocaloric ethanol-liquid diet where ethanol accounts for 35.5% of the total calories, for up to 40 days. There was no difference in body weight or liver/body weight ratio among the three groups of animals at the end of the feeding period. Hepatic and plasma triglycerides were elevated in the ethanol-treated animals only, correlated with an accumulation of lipid particles in the liver of these animals. By DNA excess hybridization, the steady state mRNA levels of apoB and apoB mRNA-editing protein relative to actin were not significantly altered. The proportion of edited apoB mRNA; i.e., apoB-48 mRNA/(apoB-48 + B-100) mRNA, increased in a time-dependent manner from approximately 50% to 100% in the ethanol-treated group. It remained unchanged in the chow- and liquid diet-fed animals. The proportion of apoB-48/apoB-100 protein synthesis was determined by [35S]methionine labeling followed by specific immunoprecipitation and SDS-polyacrylamide gel electrophoresis. The amount of newly synthesized apoB-48 increased from 30-50% to > 99% of the total apoB (apoB-48 + apoB-100). This increase in apoB-48 biosynthesis is reflected by an increase in circulating plasma apoB-48 from barely detectable to approximately 50% of total plasma apoB. Fractionation of plasma lipoproteins by fast protein liquid chromatography (FPLC) indicates that the ethanol-induced hypertriglyceridemia is completely accounted for by an increase in plasma very low density lipoprotein (VLDL). The proportion of apoB-48 as a percent of total apoB in the VLDL fraction increased from approximately 50% in controls to > 90% in ethanol-treated animals. Furthermore, there is a strong correlation between plasma triglyceride concentration and proportion of edited apoB-mRNA in the liver of ethanol-treated rats, but no direct correlation of the latter with intrahepatic triglyceride content. Ethanol-treated rats represent a new model for studying the regulation of apoB mRNA editing by dietary factors in vivo.