Effects of cholesterol uptake from high-density lipoprotein on bile secretion and 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity in perfused rat liver

Abstract

Small aliquots of rat high-density lipoproteins (HDL) (388 ± 67 nmol lipoprotein cholesterol) were labeled with [ 14C]cholesterol and administered as a bolus to perfused rat livers. Bile and perfusate samples were collected for 2 hours at 30-minute intervals. After perfusion, both the microsomes and lipid extracts were prepared from the livers. Lipid composition was examined in both liver and microsomes, and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity was evaluated in microsomes. Basal values of bile flow, lipid composition, and enzyme activity were evaluated using livers in which perfusion was discontinued before injecting the lipoprotein. In some experiments, the effect of perfusion per se was assessed by infusing saline instead of lipoprotein. After 10 minutes of lipoprotein perfusion, 50% of cholesterol administered was taken up by the perfused liver. During infusion, transient but significant increases in both bile flow and bile steroid secretion were observed. Cholesterol administration, even if rapid, represented less than 0.4% of total liver cholesterol content. However, this was enough to significantly increase the cholesterol to phospholipid ( CH PL ) molar ratio in liver microsomes and at the same time decrease HMG-CoA reductase activity. In conclusion, the main response of the perfused liver to HDL cholesterol infusion is a reduced activity of the rate-limiting enzyme in cholesterol biosynthesis, due to the shift in the microsomal CH PL molar ratio. A small proportion of the infused cholesterol enters bile as cholesterol and bile salts.