Synthesis of cholesterol from acetate in the rat was studied after injection of triton WR-1339, both in the whole animal and by the liver slice technique. Synthesis appeared to be increased 3-fold 24 hours after the injection. It was depressed after 72 hours, concurrently with a rise in the cholesterol concentration in the liver and its fall towards normal in the blood. When triton was injected into cholesterol-fed animals, or when their bile ducts were ligated, cholesterol synthesis was faster than in the untreated, normally fed controls, despite, in some instances, an elevated concentration of cholesterol in the liver.
Obstruction of the biliary tract has long been known to be accompanied by hypercholesterolemia (1). This phenomenon has been studied in the rat by Chanutin and Ludewig (2) and, more extensively, by Byers, Friedman, and their colleagues (3-7). In a recent review the latter authors have mentioned possible mechanisms involved, including altered absorption, synthesis, excretion, and destruction of cholesterol (8).The purpose of the present study was to investigate by isotopic methods the effect of bile duct ligation on cholesterol synthesis in the rat. As indices of the rate of cholesterol synthesis we used the incorporation of carboyxl carbon from 1-C14-acetate, and hydrogen from tritium-labelled water, into cholesterol in the intact animal, in liver slices, or in cell-free homogenates.In all the systems which we employed, the rate of incorporation of these isotopes into cholesterol was increased following ligation of the common bile duct. EXPERIMENTALRats utilized in these studies were of the Sprague-Dawley and Wistar strains, both males and females, weighing between 140 and 320 gin., and unless otherwise specified, were maintained on a steroid-free, fat-free diet of the following composition: casein (vitamin-free) 125 gin., sucrose 355 gln., salt mixture "W" (9) 20 tim., choline chloride 500 rag., thiamine hydrochloride i0 rag., riboflavine 10 rag., pyridoxine hydrochloride 10 rag., nicotinic acid 10 nag., calcium-d-pantothenate 20 rag., and llnoleic acid 0.47 gin. All surgical procedures were performed under ether anesthesia. Ligations of the common bile duct were made with double silk ligatures. Maintenance of obstruction was determined at autopsy by the presence of a dilated, bile-filled duct proximal to the ligatures with no evidence of leakage. The peritoneal cavities of all control animals were opened and the intestines manipulated.Isolation and Assay of Cholesterol.---Cholesterol was isolated from fiver in the following manner: 0.5 gin. of liver was hydrolyzed in 2.5 ml. of a 15 per cent solution of KOtt in 95 per cent ethanol for 16 hours at 100°C. An equal volume of water was then added, followed by extraction with four 10 ml. portions of petroleum ether (b.p. 30-60°). The extracts were combined and taken to dryness on the steam bath, the residue was dissolved in 4 ml. of 1 : 1 acetone-
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