Cellular control of cholesterol metabolism

Abstract

Cholesterol is a structural component of cell membranes in mammalian tissues. The cholesterol content of cells fluctuates within narrow limits and reflects synthesis within the cells and the rates of influx and efflux which are related to the metabolism of circulating lipoproteins. These events have been studied in cultured arterial smooth muscle cells and fibroblasts; accumulation of cholesterol within these cells is the hallmark of atherosclerosis. The cholesterol content of cells is more influenced by plasma lipoproteins than by cellular synthesis. Uptake of cholesterol into cells occurs through the binding of low density lipoprotein (LDL) to surface receptors, the internalization of the whole lipoprotein, the degradation of the lipoprotein and the release of its cholesterol. This in turn suppresses synthesis within the cell. Other lipoproteins are also taken up into smooth muscle cells, notably in cholesterol-fed animals. This uptake is enhanced by rendering the cells hypoxic. By contrast, uptake of LDL which transport the bulk of circulating cholesterol in man, is reduced in cells from subjects with the deficiency of the specific surface receptors; this leads to the accumulation of cholesterol in LDL in plasma and to an over-production of cholesterol within the cell. The removal of cellular cholesterol appears to be controlled by another lipoprotein, the high density lipoprotein (HDL). The proteins of HDL have a strong affinity for cholesterol and stimulate efflux from the cell. Furthermore, HDL interferes with the binding of LDL to cells. These interactions between HDL and LDL at the cellular level determine cholesterol homeostasis within cells. This can be translated to documented events leading to atherosclerosis in man: athe mass of the body's exchangeable cholesterol is inversely related to the concentration of plasma HDL bthe cholesterol content of some tissues varies directly with the plasma LDL and inversely with the plasma HDL concentrations cplasma LDL is raised and the HDL level reduced in severe hypercholesterolaemia dthe epidemiological probability of developing premature coronary artery disease is a direct function of the plasma LDL level and an inverse function of the plasma HDL level. Cholesterol is a structural component of cell membranes in mammalian tissues. The cholesterol content of cells fluctuates within narrow limits and reflects synthesis within the cells and the rates of influx and efflux which are related to the metabolism of circulating lipoproteins. These events have been studied in cultured arterial smooth muscle cells and fibroblasts; accumulation of cholesterol within these cells is the hallmark of atherosclerosis. The cholesterol content of cells is more influenced by plasma lipoproteins than by cellular synthesis. Uptake of cholesterol into cells occurs through the binding of low density lipoprotein (LDL) to surface receptors, the internalization of the whole lipoprotein, the degradation of the lipoprotein and the release of its cholesterol. This in turn suppresses synthesis within the cell. Other lipoproteins are also taken up into smooth muscle cells, notably in cholesterol-fed animals. This uptake is enhanced by rendering the cells hypoxic. By contrast, uptake of LDL which transport the bulk of circulating cholesterol in man, is reduced in cells from subjects with the deficiency of the specific surface receptors; this leads to the accumulation of cholesterol in LDL in plasma and to an over-production of cholesterol within the cell. The removal of cellular cholesterol appears to be controlled by another lipoprotein, the high density lipoprotein (HDL). The proteins of HDL have a strong affinity for cholesterol and stimulate efflux from the cell. Furthermore, HDL interferes with the binding of LDL to cells. These interactions between HDL and LDL at the cellular level determine cholesterol homeostasis within cells. This can be translated to documented events leading to atherosclerosis in man: athe mass of the body's exchangeable cholesterol is inversely related to the concentration of plasma HDL bthe cholesterol content of some tissues varies directly with the plasma LDL and inversely with the plasma HDL concentrations cplasma LDL is raised and the HDL level reduced in severe hypercholesterolaemia dthe epidemiological probability of developing premature coronary artery disease is a direct function of the plasma LDL level and an inverse function of the plasma HDL level.