Normalization of LDL Receptor Function by Lymphocytes of Patients with Heterozygous Familial Hypercholesterolemia After Treatment with Plasma Cholesterol Lowering Agents

Abstract

Low density lipoprotein (LDL)-dependent growth of mitogen-activated lymphocytes, inhibited in their capacity to synthesize cholesterol endogenously, can be used as an assay of functional receptors for LDL. Using this technique, abnormalities can be detected in circulating lymphocytes obtained from patients with familial hypercholesterolemia (FH). Functional lymphocyte LDL receptor activity was decreased in patients with heterozygous FH. Following treatment with the specific inhibitor of cholesterol synthesis, lovastatin, alone or in combination with a bile acid-binding resin, there was increased expression of functional lymphocyte LDL receptors in five of nine patients. Plasma LDL cholesterol levels decreased in all nine patients. Three other patients who were only studied while receiving therapy also manifested increased expression of functional lymphocyte LDL receptors. The degree of improvement in plasma LDL cholesterol did not predict the effect on lymphocyte LDL receptor function. Longitudinal studies indicated that an increase in functional LDL receptor activity could be observed with 4 weeks of therapy and persisted for at least 18 months on continuous treatment. These results provide direct evidence that therapy with lovastatin and a bile acid-binding resin can lead to increased expression of functional LDL receptors by lymphocytes in the majority (eight of 12) of patients with heterozygous FH.