Relationship of serum cholesterol to deaths from coronary heart disease in 36,662 men aged 35-37 years during an average followup period of 6 years. Each point represents the median value for 5% of the population. (From Report of the Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. NIH Publication 88-2925, 1988).
of blood cholesterol lowers the risk of CHD. Reductions in CHD risk appear to be due to multiple consequences of inhibiting the cholesterol synthesis pathway. Drug-induced inhibition of hepatic cholesterol synthesis leads to lowering of liver cholesterol concentrations and feedback up-regulation at the gene level of both HMG CoA reductase and the LDL receptor (mechanisms IV and VII in Fig. 23.2). As long as the statin is present at adequate concentration in the liver, the extra HMG CoA reductase activity is not expressed. However, the increased hepatic LDL receptor protein results in increased rates of removal of LDL particles from the circulation by the liver, lowering of blood LDL-cholesterol levels, slowing of atherosclerosis, and decreased risk of heart attack. An overview of lipoprotein metabolism and the sites where drugs can influence plasma lipoprotein levels is provided in Figure 23.2.
The reduced risk of CHD achieved with the statins may also be due to drug actions independent of lowering blood cholesterol. Many important molecules besides cholesterol are generated by intermediates in the complex cholesterol synthesis pathway. These include the isoprenes geranylgeranyl and farnesyl, which are co-valently attached to some proteins (isoprenylation) and target them to membranes where they function. The re
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