title: Identification of low density lipoprotein receptor abnormalities by assaying functional receptors on proliferating lymphocytes.
abstract: Lymphocyte proliferation stimulated by mitogenic lectins is dependent on exogenously supplied cholesterol when endogenous cholesterol synthesis is blocked with the specific inhibitor mevinolin. Lymphocytes from patients homozygous for familial hypercholesterolemia (FH) lack low density lipoprotein (LDL) receptors, and, therefore, these patients cannot use LDL cholesterol to support proliferation when endogenous sterol synthesis is blocked. Thus, LDL receptors are required for the uptake of exogenous lipoprotein cholesterol by proliferating lymphocytes. As a result, the number of functional receptors can be assessed when endogenous sterol synthesis is inhibited and when limiting concentrations of LDL are employed to support lymphocyte proliferation. Lymphocytes from patients heterozygous for LDL receptor abnormalities can be distinguished from normal lymphocytes since the former require twice the concentration of LDL for proliferation. By contrast, in hyperlipidemia not caused by FH, lymphocyte LDL receptor activity is normal, indicating that plasma cholesterol levels do not account for abnormalities in LDL receptor function assayed in this way. Therapy with cholesterol-lowering drugs, however, can alter lymphocyte LDL receptor activity in patients with heterozygous FH. Patients with heterozygous FH respond to therapy with mevinolin and a bile-acid-binding resin by lowering plasma cholesterol levels. In some patients, treatment with cholesterol-lowering plasma cholesterol levels. In some patients, treatment with cholesterol-lowering plasma cholesterol agents is also associated with normalization of functional lymphocyte LDL receptor activity, thereby providing direct evidence that therapy can alter LDL receptor expression.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Internal Medicine, University of Texas Health Science Center, Southwestern Medical School, Dallas 75235.
authors.forename: J A
authors.initials: JA
authors.lastname: Cuthbert
authors.forename: P E
authors.initials: PE
authors.lastname: Lipsky
mesh_terms: D002453:Cell Cycle; D002784:Cholesterol / Q000097:blood; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics; D008148:Lovastatin / Q000627:therapeutic use; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
chemical_list: D011973:Receptors, LDL; D002784:Cholesterol; D008148:Lovastatin