In order to investigate the relationship between bile acid pool composition and hepatic cholesterol metabolism in humans, we studied the effect of chronic feeding of chenodeoxycholic (CDCA) or ursodeoxycholic acid (UDCA) on the hepatic activity of acyl-CoA: cholesterol acyltransferase (ACAT) evaluated "in vitro". Twenty-eight gallstone patients were admitted to the study: 15 were untreated subjects, 8 were treated with UDCA (10 mg/kg/day for 15-20 days) and 5 were treated with CDCA (15 mg/kg/day for 15-20 days). A liver specimen and a bile sample were obtained during laparotomy for elective cholecystectomy. Untreated subjects had bile supersaturated with cholesterol (mean saturation index: 1.35 +/- 0.31) whereas subjects treated with either UDCA or CDCA had bile unsaturated with cholesterol (mean saturation index: 0.66 +/- 0.1 and 0.75 +/- 0.06 respectively). In all treated subjects the bile acid administered became predominant in bile. ACAT activity was 14% lower in subjects treated with UDCA and 16% lower in those treated with CDCA compared to controls; the differences did not achieve statistical significance. Microsomal cholesterol content did not differ between the groups (75.4 +/- 7.2 nmol/mg protein in control group; 86.5 +/- 7.0 nmol/mg protein in CDCA treated group; 83.4 +/- 7.0 nmol/mg protein in UDCA treated group). Our data show that the cholesterol esterifying activity of human liver is not affected by changes in bile acid pool composition.

Acyl Coenzyme A↗

PubMedDate not supplied

Regulation of bile acid synthesis in humans: studies on cholesterol 7 alpha-hydroxylation in vivo.

Over the last few years important progress has been made on the quantitation of cholesterol 7 alpha-hydroxylation, the rate-limiting step of bile acid synthesis. The use of a technique based on the determination of body water tritium enrichment after i.v. administration of [7 alpha-3H] cholesterol has allowed in vivo investigation of this step in humans in different experimental conditions. The cholesterol 7 alpha-hydroxylation rate was not affected by the administration of the hydrophilic bile acid ursodeoxycholic acid (UDCA) whereas it was significantly reduced by the more hydrophobic chenodeoxycholic acid (CDCA) and even more so by the strongly hydrophobic deoxycholic acid (DCA). The administration of cholestyramine induced a significant dose-related increase of 7 alpha-hydroxylation along with a correspondent decrease in plasma cholesterol. The administration of simvastatin exerted no effect on cholesterol 7 alpha-hydroxylation despite a marked decrease in serum cholesterol. Treatment with fibrates reduced plasma lipid levels and 7 alpha-hydroxylation rates. Hydroxylation rates were unchanged in familial hypercholesterolaemia and increased in familial combined hyperlipidaemia. These data suggest that in humans bile acid synthesis can be affected by quantitative and qualitative alterations of the enterohepatic circulation of bile acids. Changes in cholesterol 7 alpha-hydroxylation rates may be associated with alterations in plasma lipid levels, but such a relationship is ill-defined and seems to vary with the different experimental models.

Aryl Hydrocarbon Hydroxylases↗