Membrane microdomains and the regulation of HDL biogenesis.

Abstract

The major cardio-protective function of HDL is to remove excess cellular cholesterol in the process of HDL particle formation and maturation. The HDL biogenic procedure requiring protein-lipid interactions has been incompletely understood, and here we discuss recent progress and insights into the mechanism of HDL biogenesis. The initial and rate-limiting step of HDL biogenesis is the interaction between apoA-I and plasma membrane microdomains created by ATP-binding cassette transporter A1 (ABCA1) transporter. Computer simulation of molecular dynamics suggests that ABCA1 translocates phospholipids from the inner to the outer leaflet of the plasma membrane to create a transbilayer density gradient leading to the formation of an exovesiculated plasma membrane microdomain. The cryo-electron microscopy structure of ABCA1 suggests that an elongated hydrophobic tunnel formed by the extracellular domain of ABCA1 may function as a passageway to deliver lipids to apoA-I. In contrast to ABCA1-created plasma membrane microdomains, desmocollin 1 (DSC1) contained in a cholesterol-rich plasma membrane microdomain binds apoA-I to prevent HDL biogenesis. The identification of DSC1-containing plasma membrane microdomains as a negative regulator of HDL biogenesis may offer potential therapeutic avenues. Isolation and characterization of plasma membrane microdomains involved in HDL biogenesis may lead to a better understanding of the molecular mechanism of HDL biogenesis.