106 Nature Vol. 292 9 July 1981 Plasma lipoproteins and cellular metabolism

from J. S. Owen

PLASMA LIPOPROTEINS are macro­ specific cell-surface membrane receptors is transport, receptor and enzymatic molecular complexes in which lipids are an important method of regulating cellular functions are primarily determined by the bound to a variety of polypeptides (the metabolism. Plasma lipoproteins also protein constituents, there is considerable apoproteins) through non-covalent forces. appear to possess this regulatory capacity. evidence that such membrane protein Four main classes of lipoprotein are The elegant work of J. Goldstein and M. functions may be influenced by the recognized, each defined by the density at Brown at the University of Texas, Dallas properties of the fluid lipid bilayer matrix. which it floats in the ultracentrifuge - has established that cultured cells have A shift in the dynamic equilibrium between chylomicrons, very-low-density lipo­ high-affinity receptor sites which recognize membrane and lipoprotein lipids, through protein (VLDL), low-density lipoprotein the apoprotein moiety (ApoB) of LDL. abnormalities in lipoprotein lipid pattern, (LDL) and high-density lipoprotein Subsequent studies, principally by R. would therefore be expected to lead to (HDL). Although these classes vary widely Mahley and colleagues at the National changes in membrane lipid composition in size, and in lipid and apoprotein Heart and Blood Institute, Bethesda, have and so indirectly to membrane and cellular composition, they appear to have a similar shown that ApoE-containing lipoproteins, dysfunction. For example, the ratio of general structure: they are spherical including both HDLI (the HDL sub-class cholesterol to phospholipid is an important particles with a hydrophobic core of through which cholesterol may be determinant of membrane fluidity, many cholesteryl ester and triglyceride sur­ delivered to the liver) and chylomicron membrane-bound enzymes depend on rounded by a 2 nm-thick monolayer of remnants (the particles remaining after specific phospholipids for full activity, and apoprotein, cholesterol and phospholipid partial hydrolysis of core triglyceride), also phospholipid fatty acid composition may molecules. bind to the same cell-surface receptor. be a critical factor in secondary modulation Chylomicrons transport triglyceride and After binding, these various lipoproteins of fluidity and in synthesis of other fat-soluble substances from the regulate intracellular cholesterol prostaglandins. intestine while VLDL transports endo­ metabolism and receptor activity, Is there experimental evidence that this genous triglyceride from the liver. The tri­ processes dependent on cellular uptake and potential influence of plasma lipoproteins glyceride contained in these particles is degradation of lipoproteins. on cellular metabolism, through their delivered to extrahepatic tissues, thereby Current evidence suggests that cells may effects on either membrane lipid com­ providing cells with an important energy also have additional lipoprotein receptors, position or regulation of selected bio­ source. Although almost all cells can specific for the apoprotein moieties and chemical reactions, is physiologically synthesize cholesterol, several clinical and distinct from the classical 'LDL receptor', important? Support has largely been biochemical studies suggest that most and that lipoprotein occupancy of such obtained by study of those dyslipoprotein­ cellular cholesterol is derived from uptake receptors is sufficient to modulate selected aemias, associated with either genetic, and degradation of LDL. By contrast, one cellular functions without requiring pathological, hormonal or dietary distur­ function of HDL may be to transport internalization of the intact particles. bances, in which substantial changes in cholesterol from peripheral tissues to its These include the activity of membrane­ apoprotein and lipid patterns have principal site of catabolism and excretion bound enzymes such as adipocyte occurred. In this context, reports by N. in the liver. adenylate cyclase and erythrocyte Mg2+_ McIntyre and his group at the Royal Free These lipid transport processes are ATPase which are stimulated by VLDL Hospital, London on the cellular abnor­ complex; they depend on an interchange of and LDL, the enhancement of lipogenesis malities associated with the acquired constituent lipids and apoproteins amongst in fat cells by VLDL and the apparent LCAT deficiency of liver disease are of the various lipoproteins, whether by LDL-induced reduction of prostacyclin interest. Lipid changes were found in exchange collision or by specific transfer production in endothelial cells. However, erythrocytes and platelets and the proteins, and the activities of lipoprotein the type of regulation most extensively abonormalities correlated with cellular lipase, hepatic lipase and lecithin-­ studied has been the potent inhibition of dysfunction (Owen et al. J. Lipid Res. 22; cholesterol acyltransferase (LCA T). Other mitogen-induced lymphocyte proliferation 423, 1981); there was also evidence in aspects of intravascular lipoprotein meta­ by the ApoB- and ApoE-containing lipo­ patients with liver disease that their bolism being investigated include the proteins (Hui et al. J. bioi. Chern. 255; abnormal HDL, enriched in ApoE, could relationship between the various HDL sub­ 11755,1980). J. Harmony and associates at effect cellular regulation by reducing LDL classes and the mechanism by which Indiana University have shown that several uptake, by altering erythrocyte specific HDL particles remove cellular primary mitogen-induced membrane morphology and by suppressing cholesterol (Tall and Small Adv. Lipid Res. events in lymphocyte transformation, such lymphocyte proliferation. However, the 17; 1, 1980), the origin of the lipoproteins as calcium ion and cyclic GMP accumu­ majority of cells studied in such cases of producing cholesteryl ester deposition in lation and phosphatidylinositol turnover, abnormal lipoprotein composition have the macrophage-like cells of the arterial are markedly suppressed by membrane­ been isolated from the lipoprotein-rich wall (Goldstein et al. J. bioi. Chern. 255; rece:ptor binding of these apoproteins. environment of the plasma compartment 1839, 1980, and Schechter et al. J. Lipid The membrane lipid composition of cells and clearly there is a need to extend these Res. 22; 63, 1981), and the involvement of may be influenced by lipoprotein lipid observations to cells which have access only the liver in LDL and HDL clearance com position as a consequence of the ready to the lipoproteins of the extravascular (Pittman et al. Proc. natn. Acad. Sci. exchange between lipoprotein cholesterol fluid. That such investigations will be U.S.A. 76; 5345, 1979). In contrast, one and phospholipid (mainly phosphatidyl­ fruitful is suggested by the interactions of aspect of lipoprotein metabolism has been choline and sphingomyelin) and the cor­ abnormal lipoproteins with cultured cells relatively neglected: the influence of responding lipids in cellular plasma and by the poorly understood metabolic lipoproteins on cellular function by their membranes. Although cell membrane and cellular disturbances frequently regulation of selected cellular biochemical associated with those dyslipoprotein­ reactions and by their role in maintaining a aemias, such as primary and secondary normal cell membrane lipid composition. LCAT deficiency and abetalipoprotein­ The interaction of circulating hormones J. S. Owen is in the Academic Department of aemia, in which marked changes in lipid and certain non-hormonal molecules with Medicine, The Royal Free Hospital, London. and apoprotein composition occur. [;

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