LITHOGENIC DIET AND GALLSTONE FORMATION IN MICE - INTEGRATED RESPONSEOF ACTIVITIES OF REGULATORY ENZYMES IN HEPATIC CHOLESTEROL-METABOLISM

Supersaturation of bile with cholesterol is a prerequisite of the deve lopment of gallstones. With the intention to study the integrated resp onse of enzymes regulating hepatic cholesterol metabolism during galls tone formation we used an established model for the induction of chole sterol gallstone disease in mice. Ten mice were fed on a lithogenic di et containing 10 g cholesterol/kg and 5 g cholic acid/kg for 8 weeks a nd were compared with ten mice fed on a standard pellet diet. Choleste rol crystals or gallstones developed in 90% of gallbladders in treated mice. The lithogenic diet had an inhibitory effect on the rate-limiti ng enzyme of cholesterol biosynthesis, hepatic 3-hydroxy-3-methylgluta ryl-CoA (HMG-CoA) reductase (EC 1.1.1.88) activity, 39.6 (SEM 2.8) v. 171.0 (SEM 47.3) pmol/min per mg protein. Cholesterol ira-hydroxylase (EC 1.14.13.17) activity, regulating bile acid synthesis, was decrease d by 80%, and this was assumed to be due to cholic acid in the diet. T he cholesterol-enriched diet also induced a tenfold increase in choles terol esterification rate in the liver, i.e. acyl-CoA:cholesterol acyl transferase (ACAT; EC 2.3.1.26) activity. The total, as web as esteri fied, cholesterol contents of liver homogenates were significantly hig her in cholesterol- and cholic acid-treated mice and correlated well w ith the ACAT activity (r(s) 0.72 (P < 0.005), and r(s) 0.68 (P < 0.01) respectively). A significantly higher ACAT activity was obtained in m ice given cholesterol and cholic acid even when the enzyme was saturat ed with exogenous cholesterol, thus indicating an increased amount of the enzyme. The formation of gallstones is dependent on a delicate bal ance between lithogenic factors (increased absorption of cholesterol a nd reduced secretion of bile acids) and defence mechanisms (decreased synthesis and increased esterification of cholesterol). In the specifi c animal model studied here the two defence mechanisms cannot compensa te for the increased absorption of cholesterol and the reduced synthes is of bile acids.