Objective— Macrophage expression of both apolipoprotein E (apoE) and ABCA1 have been shown to modulate lipid efflux from these cells and to play an important atheroprotective role in vivo. We evaluated the relationship between apoE and ABCA1 for regulating cellular sterol efflux.

Methods and Results— ApoE-mediated, but ABCA1-independent, lipid efflux was demonstrated in 3 model systems. First, adenoviral-mediated expression of apoE in dermal fibroblasts isolated from ABCA1^−/− mice significantly increased both sterol and phospholipid efflux. Second, expression of human apoE in a macrophage cell line increased sterol efflux, and this increment in efflux was not reduced by suppressing ABCA1 expression. Third, reduction of apoE expression using an apoE small interfering RNA significantly reduced sterol efflux from ABCA1^−/− mouse peritoneal macrophages. ApoE-mediated, but ABCA1-independent, lipid efflux could be differentiated from lipid efflux that was dependent on the extracellular accumulation of secreted apoE, because exogenous cell-derived apoE stimulated efflux only from cells expressing ABCA1. Sterol efflux was usually highest in cells expressing both ABCA1 and apoE, likely representing a summation of the ABCA1-dependent and -independent pathways for apoE-mediated sterol efflux.

Conclusions— ABCA1 expression is required for apoE-mediated efflux when endogenously synthesized apoE accumulates extracellularly. Our results, however, establish the existence of an ABCA1-independent pathway for lipid efflux that requires the intracellular synthesis and/or transport of apoE.