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In a previous study the present investigators demonstrated that cholestyramine treatment (10 g/kg of diet) reduced cholesterol synthesis and lowered hepatic cholesterol levels in hamsters. In the present study, the effect of cholestyramine treatment (10 g/kg of diet) on hepatic cholesterol synthesis in hamsters was investigated further by examining the effects of the drug on hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity and gene expression. The results showed a significant decrease in the enzyme activity (31%; P less than 0.05) and a significant reduction in the hepatic 3-hydroxy-3-methylglutaryl-CoA:mevalonate ratio (40%; P less than 0.01) in cholestyramine-treated hamsters. However, the hepatic mevalonate levels were unchanged. HMG-CoA reductase gene expression was not significantly different among control, cholestyramine, and pair-fed cholestyramine groups. A significant positive correlation was observed between hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity and the 3-hydroxy-3-methylglutaryl-CoA:mevalonate ratio (r = 0.79; P less than 0.01), and a significant negative correlation was observed between hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity and mevalonate levels (r = -0.55; P less than 0.05). These observations suggest that the hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity is a major determinant of the hepatic cholesterol biosynthetic pathway, with regulation in response to changes in the hep
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