Lipoproteins and cellular cholesterol homeostasis

Cholesterol homeostasis in peripheral cells involves a balance between the influx and efflux processes. The acquisition of cholesterol by such cells is mediated by a variety of receptor and non-receptor processes involving both normal and modified lipoproteins. The offsetting efflux process is mediated by HDL and especially particles containing only apo A-I. An efficient reverse cholesterol transport by HDL of cholesterol from peripheral cells to the liver protects against the development of atherosclerosis. In cells that do not contain excess cholesterol, the cholesterol is distributed as unesterified cholesterol molecules between the plasma membrane and the membranes of the intracellular organelles. In cholesterol-loaded cells such as macrophage foam cells, the membranes became enriched in unesterified cholesterol and, in addition, cytoplasmic CE droplets and lysosomal cholesterol crystals can form. The ways in which cholesterol molecules move between intracellular sites and the plasma membrane to become available for efflux to extracellular acceptor particles are becoming known. Cholesterol molecules in the plasma membrane can desorb and diffuse through the aqueous phase and be sequestered by HDL particles. The cell cholesterol available for efflux can exist in different kinetic pools, and these pools, such as those in various domains in the plasma membrane, require further definition. The cholesterol molecules present in intracellular pools also efflux with different kinetics and by different pathways. Thus, newly synthesized cholesterol is actively transported by a vesicle system from the ER to the plasma membrane, whereas lysosomal cholesterol seems to be transported to the plasma membrane by a protein-mediated, diffusional process. Clearance of cytoplasmic CE is dependent upon the rate of turnover of the CE cycle and the magnitude of the cholesterol gradient between the plasma membrane and the extracellular acceptor particle. It can be expected that the interdependence of the pathways and the molecular mechanisms underlying the intracellular trafficking of cholesterol will be elucidated in the near future.