Low density lipoprotein causes general cellular activation with increased phosphatidylinositol turnover and lipoprotein catabolism.

Abstract

Low density lipoprotein (LDL), at concentrations high enough for receptor binding but not high enough to saturate the receptor, induces activation of phosphatidylinositot (PtdIns) turnover in a variety of cell types with various biological functions. Using both biochemical and electron microscopic studies, we have shown that blood platelets take up and degrade LDL in a manner reminiscent of phagocytic cell types. The activation of both PtdlIns turnover and LDL metabolism is inhibited by high density lipoprotein. Thus, LDL at hormonal concentrations causes general cellular activation.Since all cell types studied responded to LDL with increased PtdIns turnover and uptake of LDL cholesterol, the PtdIns cycle may also be involved in the cellular regulation of LDL cholesterol metabolism.It has recently been demonstrated that low density lipoprotein (LDL), at concentrations in the range of its dissociation constant (Kd) for receptor binding, =1 nM, rapidly affects human platelets in several ways: (i) their shape and ultrastructural morphology are transiently altered; (ii) phosphatidylinositol (PtdIns) turnover and the molar concentration of intracellular free calcium, [Ca2+]i, are increased; and (iii) thromboxane B2 formation is enhanced (1). All of these effects are inhibited by high density lipoprotein fraction 3 (HDL3), which is known to interfere with LDL binding in platelets (2).Studies with fibroblasts have shown that Ca2+-and phospholipid-dependent protein kinase C, which is activated by stimulation ofPtdIns turnover, controls the activity ofcertain enzymes involved in cellular LDL cholesterol (LDL-Chol) metabolism (3-5). This suggests an interrelationship between the PtdIns response and LDL-Chol metabolism, but it is not known whether low concentrations of LDL stimulate the PtdIns cycle in cells other than platelets. Furthermore, it remains to be clarified whether platelets, like other cells, are capable of metabolizing LDL-Chol. Although platelets, which freely exchange cholesterol with plasma under normocholesteremic conditions, are unable to synthesize cholesterol, there is an unexplained increase in the cholesterol-phospholipid ratio in familial and experimental hypercholesterolemia (6-9). Also HDL fractions are known to be internalized and degraded by platelets (10). These findings suggested to us that there might be a catabolic pathway for LDL-Chol in the platelets.We show here that the LDL-induced activation of the PtdIns cycle occurs not only in platelets but also in various cell types that metabolize LDL-Chol, including arterial smooth muscle cells, lung fibroblasts, lymphocytes, and vascular endothelial cells. We also establish that the catabolism of lipoproteins occurs not only in these cell types but also in platelets. Thus, LDL induces general cellular activation at concentrations near the Kd for receptor binding, which appears to be comparable to hormonal effects. MATERIALS AND METHODSLipoprotein Isolation. LDL (density, 1.019-1.063 g/ml) and HDL3 (density, 1.125-1.3 g/ml) were isolate...

Chemokine Receptor CCR2 Expression and Monocyte Chemoattractant Protein-1–Mediated Chemotaxis in Human Monocytes

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