High density lipoprotein biogenesis, cholesterol efflux, and immune cell function

Abstract

This review provides a summary of recent research on the role of high-density lipoprotein (HDL)/apolipoprotein A-I cholesterol efflux and immune cell function. Plasma concentrations of HDL have been known to inversely correlate with risk for coronary vascular disease. Bulk transport of HDL cholesterol from the peripheral tissues to the liver is a major pathway, termed reverse cholesterol transport, responsible for maintaining whole body cholesterol homeostasis. In addition to participating in this pathway, HDL and apolipoprotein A-I exert anti-inflammatory effects through different pathways. One pathway that seems to be important in atherosclerosis and autoimmunity is its role in modulation of T cell activation. HDL/apolipoprotein A-I helps regulate cell signaling by accepting membrane cholesterol from ATP binding cassette transporter A1 on immune cells and, thereby, fine tuning the amount of cholesterol present in plasma membrane lipid rafts.

Figure

A Mechanism for assembling nascent high-density lipoprotein (nHDL) particles. ATP binding cassette transporter (ABC) A1 coordinates the removal of excess membrane free cholesterol (FC) and sphingomyelin (SM) and thus lowers the amount of lipid raft on the plasma membrane. ABCA1 is not located in lipid rafts (regions enriched in FC and SM), but these regions are undoubtedly the source of lipids transferred to nHDL. Biogenesis of nHDL particles by ABCA1 begins when apolipoprotein (apo) A-I binds at the membrane surface, possibly to accessory protein(s), and then moves to ABCA1. If lipid or apoA-I are unavailable then a lipid-poor nHDL of <6 nm diameter is released. If a second apoA-I is added then the newly formed 2-apoA-I/ABCA1 complex can package small amounts of lipid. This complex is either released as a 7.5-nm -diameter nHDL or it adds a third molecule of apoA-I. At this point it can load more lipid to release an ≈9- to 11-nm-diameter nHDL into the medium. Reprinted with permission.