ATP binding cassette transporter ABCA1 modulates the secretion of apolipoprotein E from human monocyte-derived macrophages

Apolipoprotein E (apoE) produced by macrophages in the arterial wall protec ts against atherosclerosis, but the regulation of its secretion by these ce lls is poorly understood. Here we investigated the contribution of the aden osine triphosphate binding cassette transporters ABCA1 and ABC8 to the secr etion of apoE from either primary human monocyte-derived macrophages (HMDM) or human THP1 macrophages. During incubations of up to 6 h, apoE secretion from both THP1 macrophages and HMDM was stimulated by 8-Br-cAMP, which act ivates ABCA1 expression. The putative ABCA1 inhibitor glyburide and antisen se oligonucleotides directed against ABCA1 mRNA significantly reduced apoE secretion from THP1 macrophages and HMDM. Antisense oligonucleotides direct ed against ABC8 mRNA also inhibited apoE secretion, although this inhibitio n was less pronounced and consistent than in the case of ABCA1. ApoE secret ion from HMDM of ABCA1-deficient patients with Tangier disease was also dec reased. ApoE mRNA expression was not affected by inhibition of ABCA1 or ABC 8 in normal HMDM or the lack of functional ABCA1 in HMDM from Tangier disea se patients. Inhibition of ABCA1 in HMDM prevented the occurrence of anti-a poE-immunoreactive granular structures in the plasma membrane. We conclude that ABCA1 and, to a lesser extent, ABC8 both promote secretion of apoE fro m human macrophages.