INHIBITION OF HEPATIC ACAT DECREASES APO-B SECRETION IN MINIATURE PIGS FED A CHOLESTEROL-FREE DIET

To test the hypothesis that hepatic cholesteryl ester is involved in t he regulation of apolipoprotein (apo) B secretion into plasma, apoB ki netic studies were performed in six control miniature pigs and in six pigs after a 21-day administration of the acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor DuP 128 (2.2 mg.kg(-1).d(-1) IV), Pig s were fed low-fat, cholesterol-free diets. Total plasma cholesterol, triglyceride, very-low-density lipoprotein (VLDL) triglyceride, and lo w-density lipoprotein (LDL) cholesterol decreased 18%, 29%, 40%, and 2 6% respectively (P<.03). I-131-VLDL and I-125-LDL were injected simult aneously into each animal, and apoB kinetics were analyzed by using mu lticompartmental analysis (SAAM30). VLDL apoB pool size decreased sign ificantly by 60% (0.32 versus 0.84 mg/kg), which was due to a 65% redu ction in the VLDL apoB production or secretion rate (1.03 versus 2.94 mg.kg(-1).h(-1)). The fractional catabolic rate was unchanged. LDL apo B pool size decreased nonsignificantly by 18% (5.61 versus 6.90 mg/kg) due entirely to a 24% decrease in production rate (0.26 versus 0.34 m g.kg(-1).h(-1)). At necropsy, hepatic microsomal ACAT activity decreas ed by 68% (0.28 versus 0.88 nmol.min(-1).mg(-1); P<.0002). Although an increase in hepatic free cholesterol leading to a decreased LDL recep tor expression might be expected, this did not occur. The concentratio n of hepatic cholesterol and the LDL apoB fractional catabolic rate we re unaffected by DuP 128. In addition, the concentration of hepatic tr iglyceride and the activity of diacylglycerol acyltrans- ferase were n ot altered by DuP 128, indicating a lack of effect of DuP 128 on hepat ic triglyceride metabolism. We conclude that inhibition of hepatic cho lesteryl ester synthesis in vivo decreases apoB secretion into plasma.