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.)
The prevalence of gallstone disease and associated factors in the entire population of subjects aged 15-65 years born and resident in Chianciano Terme (Siena - Tuscany) was examined in the years 1985 ...and 1986. The investigation included gallbladder ultrasonography, administration of a questionnaire on personal and family history, physical examination and blood chemistry. A total of 1809 subjects (attendance rate 87.7%) participated in the study. Personal history and physical examination showed that Chianciano inhabitants have a low prevalence of obesity (4.3%) and only 4.4% of the female population had more than two pregnancies. Overall prevalence of gallstone disease (cholecystectomy + cholelithiasis) was 5.9% (3.7% for males and 8.4% for females). Age standardized relative risk of gallstone disease for females was 2.25 (95% confidence limits = 1.68-2.68). Prevalence of cholelithiasis was 3.5% (2.7% for males and 4.2% for females). Prevalence of gallstone disease increased with increasing age in both sexes, being extremely low in the age interval of 15-29 years (0.25%). The overall gallstones/cholecystectomy ratio was found to be lower (1:1) in females than in males (2.7:1). Although subjects with gallstones reported more frequently biliary colics and non-specific dyspeptic symptoms, the diagnostic power of all symptoms in identifying cholelithiasis was very poor due to low sensitivity. Only one third of subjects with gallstones was aware of having the disease. Age, obesity and number of pregnancies were positively associated with gallstone disease in univariate analyses. The association with obesity and parity disappeared in multivariate analysis. Blood lipids and glucose were not associated with the disease both in univariate and multivariate analyses. Our data show that the prevalence of gallbladder disease in Chianciano is lower than that previously reported in Italy. This difference could be related to a lower prevalence of obesity and to a smaller number of pregnancies or to the effect of environmental and genetic factors.
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 ⊇-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 occuludable 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.
The rates of cholesterol 7α‐hydroxylation (the first and rate‐limiting step of bile acid synthesis from cholesterol) were evaluated in vivo in patients administered bile acids with different ...structural properties, cholestyramine or simvastatin, a competitive inhibitor of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase. Twenty‐three subjects, with normal hepatic and intestinal functions, were studied in basal conditions and after one of the following treatment schedules, lasting 4 to 6 weeks: cholestyramine, 4 and 12 gm/day (four patients); ursodeoxycholic acid, 9 to 11 mg/kg/day (four patients); chenodeoxycholic acid, 12 to 15 mg/kg/day (five patients); deoxycholic acid, 8 to 10 mg/kg/day (four patients); and simvastatin, 40 mg/day (six patients). 7α‐Hydroxylation of cholesterol was assayed by measuring the increase in body water tritium after intravenous bolus of cholesterol tritiated at the 7α position. Plasma bile acid composition, evaluated by gas‐liquid chromatography, revealed a substantial enrichment of the recirculating pool by the administered bile acid, whereas treatment with cholestyramine decreased the content of dihydroxylated bile acids. Cholesterol 7α‐hydroxylation increased in a dose‐related manner after cholestyramine, in parallel with a decrease of cholesterol in total plasma and low‐density lipoproteins (1.006 to 1.063 gm/ml). Hydroxylation rates decreased by an average of 47% with chenodeoxycholic acid and by an average of 78% with deoxycholic acid; ursodeoxycholic acid treatment did not affect 7α‐hydroxylation significantly. Simvastatin markedly reduced plasma total and low‐density lipoproteincholesterol but exerted no change on 7α‐hydroxylation rates. Our results support the existence of a feedback inhibition exerted on cholesterol 7α‐hydroxylation (and consequently on bile acid synthesis) by hydrophobic bile acids returning to the liver through the enterohepatic circulation. The finding emphasizes the importance of the physicochemical properties of bile acids in the regulation of hepatic cholesterol balance. Under these experimental conditions, inhibition of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase and presumably reduced availability of newly synthesized cholesterol are not critical for bile acid synthesis. (HEPATOLOGY 1991;14:830–837).
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