Assessment of functional low-density lipoprotein receptor activity on lymphocytes of normal subjects and patients with familial hypercholesterolemia.

In FH, abnormalities of the gene encoding the receptor for LDL lead to hypercholesterolemia and premature atherosclerosis. A method to identify LDL receptor defects using peripheral blood lymphocytes has been developed. When endogenous synthesis of cholesterol was blocked, proliferation of mitogen-stimulated normal human lymphocytes was markedly inhibited unless an exogenous source of sterol was supplied. When exogenous sterol was provided as a plasma lipoprotein, LDL receptor-mediated interaction with apolipoprotein-B or -E was essential for the provision of cholesterol to normal human lymphocytes. Thus, functional LDL receptors were necessary to permit proliferation of normal lymphocytes in these cultures. Lymphocytes from patients heterozygous for abnormalities in the LDL receptor gene can be distinguished from normal lymphocytes by their diminished functional LDL receptor activity. Of interest, following treatment with plasma cholesterol-lowering agents, functional lymphocyte LDL receptor activity normalized in some but not all patients with heterozygous FH, whereas plasma LDL cholesterol levels decreased in all patients. These results suggest that therapy with plasma cholesterol-lowering agents can lead to increased expression of LDL receptors by lymphocytes in the majority of patients with heterozygous FH. The failure of some heterozygous FH patients to increase functional LDL receptor activity after prolonged therapy indicates that there is heterogeneity in these patients despite a similar capacity of the therapy to decrease plasma LDL cholesterol. Variability in the expression of the normal LDL receptor gene in individual T lymphocytes may account for some of these findings.