TY - JOUR
T1 - Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol
AU - Reihner, E.
AU - Rudling, M.
AU - Stahlberg, D.
AU - Berglund, Lars
AU - Ewerth, S.
AU - Bjorkhem, I.
AU - Einarsson, K.
AU - Angelin, B.
PY - 1991
Y1 - 1991
N2 - Background: Inhibitors of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are now used frequently to treat hypercholesterolemia. We studied the effects of specific inhibition of cholesterol synthesis by one of these agents (pravastatin) on the hepatic metabolism of cholesterol in patients with gallstone disease who were scheduled to undergo cholecystectomy. Methods: Ten patients were treated with pravastatin (20 mg twice a day) for three weeks before cholecystectomy; 20 patients not treated served as controls. A liver specimen was obtained from each patient at operation, and the activities of rate-determining enzymes in cholesterol metabolism as well as low-density-lipoprotein (LDL)-receptor binding activity were determined. Results: Pravastatin therapy reduced plasma total cholesterol by 26 percent and LDL cholesterol by 39 percent (p < 0.005). Serum levels of free lathosterol, a precursor of cholesterol whose concentration reflects the rate of cholesterol synthesis in vivo, decreased by 63 percent (p < 0.005), indicating reduced de novo biosynthesis of cholesterol. Microsomal HMG-CoA reductase activity, when analyzed in vitro in the absence of the inhibitor, was increased 11.8-fold (1344 ± 311 vs. l05 ± l4 pmol per minute per milligram of protein in the controls ; p < 0.001). The expression of LDL receptors was increased by 180 percent (p < 0.005), whereas the activities of cholesterol 7α-hydroxylase (which governs bile acid synthesis) and of acyl-coenzyme A:cholesterol O-acyltransferase (which regulates cholesterol esterification) were unaffected by treatment. Conclusions: Inhibition of hepatic HMG-CoA reductase by pravastatin results in an increased expression of hepatic LDL receptors, which explains the lowered plasma levels of LDL cholesterol.
AB - Background: Inhibitors of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are now used frequently to treat hypercholesterolemia. We studied the effects of specific inhibition of cholesterol synthesis by one of these agents (pravastatin) on the hepatic metabolism of cholesterol in patients with gallstone disease who were scheduled to undergo cholecystectomy. Methods: Ten patients were treated with pravastatin (20 mg twice a day) for three weeks before cholecystectomy; 20 patients not treated served as controls. A liver specimen was obtained from each patient at operation, and the activities of rate-determining enzymes in cholesterol metabolism as well as low-density-lipoprotein (LDL)-receptor binding activity were determined. Results: Pravastatin therapy reduced plasma total cholesterol by 26 percent and LDL cholesterol by 39 percent (p < 0.005). Serum levels of free lathosterol, a precursor of cholesterol whose concentration reflects the rate of cholesterol synthesis in vivo, decreased by 63 percent (p < 0.005), indicating reduced de novo biosynthesis of cholesterol. Microsomal HMG-CoA reductase activity, when analyzed in vitro in the absence of the inhibitor, was increased 11.8-fold (1344 ± 311 vs. l05 ± l4 pmol per minute per milligram of protein in the controls ; p < 0.001). The expression of LDL receptors was increased by 180 percent (p < 0.005), whereas the activities of cholesterol 7α-hydroxylase (which governs bile acid synthesis) and of acyl-coenzyme A:cholesterol O-acyltransferase (which regulates cholesterol esterification) were unaffected by treatment. Conclusions: Inhibition of hepatic HMG-CoA reductase by pravastatin results in an increased expression of hepatic LDL receptors, which explains the lowered plasma levels of LDL cholesterol.
KW - cholesterol biosynthesis
KW - HMG-CoA-reductase inhibition
KW - liver enzymes
KW - pravastatin
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M3 - Article
AN - SCOPUS:0025771935
VL - 109
SP - 53
EP - 60
JO - Fortschritte der Medizin
JF - Fortschritte der Medizin
SN - 0015-8178
IS - 8
ER -