TY - JOUR
T1 - Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol
AU - Reihnér, Eva
AU - Rudling, Mats
AU - Ståhlberg, Dagny
AU - Berglund, Lars
AU - Ewerth, Staffan
AU - Björkhem, Ingemar
AU - Einarsson, Kurt
AU - Angelin, Bo
PY - 1990/7/26
Y1 - 1990/7/26
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. 105±14 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. 105±14 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.
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M3 - Article
C2 - 2114543
AN - SCOPUS:0025345124
VL - 323
SP - 224
EP - 228
JO - New England Journal of Medicine
JF - New England Journal of Medicine
SN - 0028-4793
IS - 4
ER -