The rates of cholesterol 7-alpha-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). 7-alpha-Hydroxylation of cholesterol was assayed by measuring the increase in body water tritium after intravenous bolus of cholesterol tritiated at the 7-alpha 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 7-alpha-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 7-alpha-hydroxylation significantly. Simvastatin markedly reduced plasma total and low-density lipoprotein-cholesterol but exerted no change on 7-alpha-hydroxylation rates. Our results support the existence of a feedback inhibition exerted on cholesterol 7-alpha-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.
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|Anno di pubblicazione:||1991|
|Titolo:||Regulation of bile acid synthesis in humans: effect of treatment with bile acids, cholestyramine or simvastatin on cholesterol 7 alpha-hydroxylation rates in vivo.|
|Autori:||M. BERTOLOTTI; N. ABATE; P. LORIA; M. DILENGITE; F. CARUBBI; A. PINETTI; A. DIGRISOLO; N. CARULLI|
|Appare nelle tipologie:||Articolo su rivista|
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