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Abstract

To test whether de novo synthesis of cholesterol is a limiting factor for bile acid synthesis, we studied the acute effect of simvastatin, an inhibitor of HMG–coenzyme A reductase (the limiting step of cholesterol synthesis) on bile acid synthesis and biliary lipid secretion in subjects with interrupted enterohepatic circulation. In these conditions bile acid synthesis is derepressed and is assumed to equal biliary bile acid secretion. Five cholecystectomized patients fitted with T-tubes were studied. All subjects were administered simvastatin (80 mg as a single dose) 5 days after surgery. Bile was collected in 3-hr intervals for 15 hr before and 30 hr after the administration of the drug. During the experiment we kept the enterohepatic circulation of bile acid interrupted by inflating an occludable balloon inserted, during cholecystectomy, in the common bile duct. Simvastatin induced significant decreases of plasma total and low density lipoprotein cholesterol concentrations, from 163 ± 29 mg/dl and 97 ± 24 mg/dl of the pretreatment value to 144 ± 30 mg/dl and 82 ± 22 mg/dl 18 hr after simvastatin administration, respectively. Bile flow tended to increase after simvastatin, and the mean values from the third to the 15th hour after simvastatin administration (22.1 ± 1.9 ml/hr) were significantly greater than the mean values of the pretreatment period (19.9 ± 2.8 ml/hr). Concomitantly biliary bile acid, cholesterol and phospholipid concentrations fell from basal values of 15.9 ± 5.1, 2.3 ± 0.3 and 5.5 ± 0.3 mmol/L to mean values, after treatment, of 9.0 ± 3.5, 1.9 ± 0.5 and 3.0 ± 0.9 mmol/L, respectively. Cholesterol saturation index increased from a mean value of 1.51 ± 0.31 in the pretreatment period to 1.98 ± 0.52 after simvastatin. Bile acid output decreased from a mean pretreatment value of 308.0 ± 79.1 μmol/hr to 191.9 ± 69.2 μmol/hr after simvastatin administration. Secretion rates of phospholipids decreased to a lesser extent, whereas cholesterol output remained constant. No correlation was found between bile acid output and bile flow, phospholipid secretion and cholesterol secretion. A significant correlation was present between phospholipid and cholesterol secretion. Our data show that, in conditions of derepressed bile acid synthesis, acute inhibition of HMG–coenzyme A reductase activity induces decreased bile acid synthesis and excretion. Our findings may suggest that the availability of newly synthesized cholesterol is a critical factor for bile acid synthesis and secretion but not for cholesterol secretion; alternatively HMG–coenzyme A reductase and cholesterol 7α-hydroxylase, the rate-limiting step of bile acid synthesis, may be coordinately regulated at the transcriptional level. (HEPATOLOGY 1994;19:882–888.)