Most mammalian somatic cells are unable to catabolize
cholesterol and therefore need to export it in order to maintain
sterol homeostasis. This mechanism may also function to reduce excessively accumulated
cholesterol, which would thereby contribute to prevention or cure of the initial stage of atherosclerotic vascular lesion.
High-density lipoprotein (HDL) has been believed to play a main role in this reaction based on epidemiological evidence and in vitro experimental data. At least two independent mechanisms are identified for this reaction. One is non-specific diffusion-mediated
cholesterol 'efflux' from cell surface.
Cholesterol molecules desorbed from cells can be trapped by various extracellular acceptors including various
lipoproteins and
albumin, and extracellular
cholesterol esterification mainly on HDL may provide a driving force for the net removal of cell
cholesterol by maintaining a
cholesterol gradient between
lipoprotein surface and cell membrane. The other is
apolipoprotein-mediated process to generate new HDL by removing cellular
phospholipid and
cholesterol. The reaction is initiated by the interaction of
lipid-free or
lipid-poor helical
apolipoproteins with cellular surface resulting in assembly of HDL particles with cellular
phospholipid and incorporation of cellular
cholesterol into the HDL being formed. Thus, HDL has dual functions as an active
cholesterol acceptor in the diffusion-mediated pathway and as an
apolipoprotein carrier for the HDL assembly reaction. The impairment of the
apolipoprotein-mediated reaction was found in
Tangier disease and other familial HDL deficiencies to strongly suggest that this is a main mechanism to produce plasma HDL. The causative mutations for this defect was identified in
ATP binding cassette transporter protein A1, as a significant step for further understanding of the reaction and
cholesterol homeostasis.