CONTRIBUTION OF NEWLY SYNTHESIZED CHOLESTEROL TO RAT PLASMA AND BILE DETERMINED BY MASS ISOTOPOMER DISTRIBUTION ANALYSIS - BILE-SALT FLUX PROMOTES SECRETION OF NEWLY SYNTHESIZED CHOLESTEROL INTO BILE

To quantify the contribution of newly synthesized cholesterol to total plasma and biliary cholesterol under physiological conditions, unrest rained rats were infused intravenously with [1-C-13]acetate (0.6 mmol/ h per kg) from 12:00 to 24:00 h, and fractional and absolute cholester ol-synthesis rates were determined by mass isotopomer distribution ana lysis (MIDA). As bile diversion leads to changes in cholesterol metabo lism, rats were equipped with permanent catheters in the bile duct and duodenum, allowing sampling of small amounts of bile from an intact e nterohepatic circulation. For comparison, rats with chronic bile diver sion were also studied. Fractional synthesis of plasma cholesterol was 10.8 +/- 1.7% (mean +/- S.D.) after 12 h in rats with intact circulat ion. Fractional synthesis of biliary cholesterol was significantly hig her than that of plasma cholesterol, i.e. 16.5 +/- 2.0% (P < 0.05) aft er 12 h. In contrast, no differences between fractional synthesis of c holesterol in plasma and bile were found in bile-diverted animals (31. 8 +/- 2.1 and 33.1 +/- 3.3% respectively after 12 h). The calculated a bsolute rate of cholesterol biosynthesis increased from 53 +/- 10 to 2 21 +/- 19 mu mol/day per kg after bile diversion. A comparison of MIDA results with those obtained from balance studies indicated that MIDA does not assess total body synthesis in rats, presumably because of in complete equilibration of newly synthesized molecules with cholesterol in the plasma compartment. These studies demonstrate that the contrib ution of newly synthesized cholesterol to biliary cholesterol is highe r than to plasma cholesterol under physiological conditions, probably reflecting bile-salt-induced secretion of newly formed cholesterol by the periportal hepatocytes.