Regulation of LDL receptors in vivo.

The information reviewed here indicates that LDL receptor activity in vivo is regulated in normal animals and probably in normal humans. Furthermore, LDL receptor activity is also regulated in patients with heterozygous Familial Hypercholesterolemia. Our experiments in patients with this disease indicate that one can exploit the normal regulation of receptor synthesis to stimulate the single normal gene in these patients to produce an increased number of LDL receptors. This stimulation can be accomplished by manipulating the intracellular cholesterol pools in the liver with drugs that inhibit HMG-CoA reductase and by maneuvers that result in bile acid depletion. These therapeutic measures are most effective when combined. Such therapy is likely to be beneficial, particularly since the results of the Lipid Research Clinics Primary Intervention Trial using the bile acid sequestrant, cholestyramine, have demonstrated that lowering LDL-cholesterol levels with this drug also lowers the incidence of coronary heart disease. In a broader sense, the success of this regulatory manipulation suggests that other genetic diseases may be treated by manipulation of regulatory signals that control the rates of synthesis of gene products.