Defects of receptor-mediated low density lipoprotein catabolism in homozygous familial hypercholesterolemia and hypothyroidism in vivo.

Abstract

The role of low density lipoprotein (LDL) receptors in the pathogenesis of hereditary and acquired forms of hypercholesterolemia has been investigated in vivo by simultaneously determining total and receptor-independent LDL catabolism with "MI-labeled LDL and "'I-labeled LDL coupled with cyclohexanedione. Receptor-mediated catabolism of LDL, determined as the difference between the turnover of 125I and 1311, was found to be virtually absent in two homozygotes with familial hypercholesterolemia and markedly reduced in a hypothyroid patient. Treatment of the latter with L-thyroxine markedly stimulated receptor-mediated catabolism and reduced LDL levels as did cholestyramine administration in a control subject. Reduction of LDL levels by plasma exchange in a control subject and homozygote had no such effect. These results demonstrate the existence of an intrinsic and almost total defect of receptor-mediated LDL catabolism in homozygous familial hypercholesterolemia and demonstrate an analogous but reversible abnormality in hypothyroidism.Hypocatabolism of low density lipoprotein (LDL) characterizes both familial hypercholesterolemia (FH) and hypothyroidism (1, 2). Studies with cultured fibroblasts have revealed an inherited deficiency of LDL receptors in FH, more marked in homozygotes than in heterozygotes, which has been assumed to be the cause of the catabolic defect in vivo (3, 4). Stimulation of high affinity binding and degradation of LDL in normal fibroblasts by triiodothyronine (5) suggests the possibility of an analogous but acquired deficiency of LDL receptors in hypothyroidism. Recently, Shepherd et al. (6) provided in vivo evidence of a decrease in receptor-mediated LDL catabolism in FH heterozygotes, using the technique developed by Mahley et al. (7). This involves the simultaneous administration of 125I-labeled native LDL (l2I-LDL) and '311-labeled LDL (131I-LDL) treated with 1,2-cyclohexanedione (Chd); the latter modification blocks arginine residues and thus inhibits binding of LDL to receptors on fibroblasts and smooth muscle cells (8). Using this approach, we have been able to demonstrate the virtual absence of receptor-mediated LDL catabolism in homozygous FH and the presence of a similar but reversible abnormality in hypothyroidism. Our observations, published previously only as abstracts (9, 10), help validate a novel method ofquantitating receptor-mediated LDL catabolism and illustrate the importance of that pathway in regulating serum cholesterol levels in man.SUBJECTS AND METHODS Two male FH homozygotes (M.M., D.L.), both ages 16 years and with receptor-defective fibroblasts on established criteria (11), whose clinical details are given elsewhere (12), were studied after having discontinued cholesterol-lowering drugs and plasma exchange for 5-6 wk. A 30-year-old woman (E. P.) with overt primary hypothyroidism was studied twice, before and after being rendered euthyroid by a 6-wk treatment with L-thyroxine (0.2 mg/day). Two of the authors, both normolipidemic men, aged 34 and 47, act...

Circulating MCP-1 levels shows linkage to chemokine receptor gene cluster on chromosome 3: the NHLBI Family Heart Study follow-up examination

“…14 15 This study provides preliminary evidence linking genetic variation in a receptor to circulating levels of its ligand, as previously demonstrated for the LDL receptor. 16,17 CCR2 expression was significantly correlated with plasma LDL and inversely with high-density lipoprotein and expression was increased 2.4-fold in monocytes from hypercholesterolemic patients compared to controls. Furthermore, estrogen therapy reduced CCR2 expression in hypercholesterolemic postmenopausal women compared to normocholesterolemic women.…”

Thyroid Disease and the Heart

“…The reported mechanisms for the development of hypercholesterolemia in hypothyroidism include decreased fractional clearance of LDL by a reduced number of LDL receptors in the liver in addition to decreased receptor activity. 64,69,70 The catabolism of cholesterol into bile is mediated by the enzyme cholesterol 7␣-hydroxylase. 71 This liver-specific enzyme is negatively regulated by T 3 and may contribute to the decreased catabolism and increased levels of serum cholesterol associated with hypothyroidism.…”

Impaired receptor-mediated catabolism of low density lipoprotein in the WHHL rabbit, an animal model of familial hypercholesterolemia

“…Subtraction of the FCR for chemically modified LDL from the FCR for native LDL gives an estimate of the FCR attributable to receptor-mediated catabolism of LDL. Such studies in normal humans indicate that 20-50% of the total FCR for LDL is attributable to the LDL receptor (5,8). In FH heterozygotes with about half the normal number of LDL receptors, the portion of the FCR for LDL attributable to the LDL receptor drops to about halfofthe nonnal value (5, 6), and in FH homozygotes essentially no LDL is cleared via the LDL receptor (8).…”

“…The latter include methyl-LDL and cyclohexandione-LDL which do not bind to the LDL receptor (5)(6)(7)(8)(9)(10)(11). In these studies, native and chemically modified LDL-each radiolabeled with a different isotope of iodine-are simultaneously injected into animals or humans and the fractional catabolic rate (FCR) for each is determined.…”

“…Such studies in normal humans indicate that 20-50% of the total FCR for LDL is attributable to the LDL receptor (5,8). In FH heterozygotes with about half the normal number of LDL receptors, the portion of the FCR for LDL attributable to the LDL receptor drops to about halfofthe nonnal value (5,6), and in FH homozygotes essentially no LDL is cleared via the LDL receptor (8). Similar studies in normal rats, monkeys, and rabbits indicate that the LDL receptor mechanism accounts for "50% of the total FCR for LDL in these species (7,(9)(10)(11) The publication costs ofthis article were defrayed in part by page charge payment.…”