HDL cholesterol and LDL receptor activity

Atherosclerosis, 49 (1983) 215-217 Elsevier Scientific Publishers Ireland, Ltd.

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ATH 03403

Letter to the Editors

HDL Cholesterol and LDL Receptor Activity Dear Editors,

In recent years much research has been directed at the receptors for low density lipoprotein (LDL), which are found in the plasma membranes of many cell types. Such receptors have been shown to mediate the catabolism of up to 80% of plasma LDL, the principal carrier of plasma cholesterol in man. In familial hypercholesterolaemia (FH), a dominantly inherited disorder, a total or partial deficiency of LDL receptor activity produces high plasma LDL concentrations, leading to accelerated atherosclerosis and premature death from coronary heart disease [l]. To investigate the inheritance of LDL receptor activity, and its influence on plasma LDL concentration in healthy subjects, we have measured the LDL receptor activity of blood lymphocytes isolated from normal monozygotic and dizygotic twins. Lymphocytes were obtained from defibrinated blood by density gradient centrifugation, and incubated in lipoprotein-deficient medium for 72 h to elicit maximal LDL receptor synthesis. The ability of the cells to degrade 1251-labelled human LDL was then measured during a 6-h incubation at 37’C. In this way the LDL receptor activity of human blood lymphocytes was shown to be strongly inherited [2]. When pooling the data from all subjects (n = 86) no statistically significant correlation existed between LDL cholesterol concentration in vivo and maximal LDL receptor activity in vitro. Unexpectedly, however, a negative correlation was found between LDL receptor activity and high density lipoprotein (HDL) cholesterol concentration in vivo (r = -0.26; P < 0.01). Since the series of twins investigated did not show a wide scatter of plasma LDL concentration, we have since reexamined the relation of lipoprotein levels to LDL receptor activity in 364 healthy male volunteers aged 25-55 yrs. After a preliminary screening, the maximal LDL receptor activity of blood lymphocytes in vitro was measured in subjects from the top, modal and bottom deciles of plasma cholesterol concentration, using techniques identical to those used in the first study. Although a lo-fold range of LDL receptor activity was found, no correlation existed between this and the LDL cholesterol concentration. A significant negative correlation was again found, however, between LDL receptor activity and HDL cholesterol (see Fig. 1). The absence of an association between the LDL receptor activities of lymphocytes and the plasma LDL concentration in either of these studies is compatible with the results of a previous study of fibroblasts [3]. To the extent that these measurements may reflect the receptor activity of other cells, they suggest that the rate of LDL production, rather than the fractional rate of receptor-mediated catabolism, may be 0021-9150/83/.$03.00

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Fig. 1. The relationship between HDL cholesterol concentration activity of blood lymphocytes in vitro in 81 healthy men.

in viva and the maximum

LDL receptor

the major determinant of LDL concentration in healthy humans. The unexpected negative associations between HDL cholesterol and receptor activity are difficult to explain. It is known, however, that the more variable of the two major subfractions of HDL (HDL,) contains a subclass which is rich in apoprotein E, and has an affinity for the LDL receptor which is greater even than that of LDL [4]. The function of this subclass has yet .to be identified, but there is evidence that it may be involved in the removal of cholesterol from macrophages [5]. Our unexpected findings on LDL, HDL and LDL receptors in two studies, therefore, raise intriguing questions about the role of the so-called LDL receptor in human lipoprotein metabolism. References 1 Goldstein, J.L. and Brown, M.S. In: J.B. Stanbury, J.B. Wyngaarden, D.S. Fredrickson et al. (Eds.), The Metabolic Basis of Inherited Disease, 5th edition, McGraw-Hill Co, New York, NY, 1983, p. 672. 2 Weight, M., Cortese, C., Sule, U., Miller N.E. and Lewis, B., Heritability of the low density lipoprotein receptor activity of human blood mononuclear cells - Studies in normolipidaemic adult male twins, Clin. Sci., 62 (1982) 397. 3 Maartmann-Moe, K., Magnus, P. Bsrresen, A. and Berk, K., Low density lipoprotein receptor activity in cultured fibroblast from subjects with or without ischemic heart disease (in the absence of familial hypercholesterolaemia), Clin. Genet., 20 (1981) 337. 4 Innerarity, T.L. and Mahley, R.W., Enhanced binding by cultured human fibroblasts of ape-E-containing lipoproteins as compared to low density lipoproteins, Biochemistry, 17 (1978) 1440.

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5 Basu, SK., Hd, Y.K., Brown, MS., Bilheimer, D.W., Anderson, R.G.W. and Goldstein, G.L., Biochemical and genetic studies of the apoprotein E secreted by mouse macrophages and human monocytes, J. Biol. Chem., 257 (1982) 9788. Department of Chemical Pathology and Metabolic Disorders, SI. Thomas’ Hospital Medical School, London SE1 7EH (Greai Britain)

(Received (Accepted

1 June, 1983) 23 June, 1983)

C. Cortese N.E. Miller C.B. Marenah B. Lewis