Rab8 regulates ABCA1 cell surface expression and facilitates cholesterol efflux in primary human macrophages.
OBJECTIVE
ATP-binding cassette transporter A1 (ABCA1) is thought to lipidate apolipoprotein A-I (apoA-I) at the plasma membrane, with endosomal cholesterol contributing as substrate. The mechanisms of ABCA1 surface delivery are not well understood. We have shown that Rab8 regulates endosomal cholesterol removal to apoA-I in human fibroblasts. Here, we investigated whether Rab8 plays a role in ABCA1 plasma membrane expression and cholesterol removal in primary human macrophages.


RESULTS
We found that Rab8 was abundantly expressed in human atherosclerotic lesional macrophages and upregulated on lipid loading of macrophages in vitro. Adenoviral overexpression of Rab8 increased ABCA1 protein levels and reduced cholesterol deposition in macrophage foam cells incubated with apoA-I. Depletion of Rab8 decreased the fraction of ABCA1 at the plasma membrane and inhibited the efflux of lipoprotein-derived endosomal cholesterol to apoA-I. In Rab8-depleted cells, ABCA1-GFP localized in beta1 integrin and transferrin receptor containing recycling organelles.


CONCLUSIONS
Rab8 reduces foam cell formation by facilitating ABCA1 surface expression and stimulating endosomal cholesterol efflux to apoA-I in primary human macrophages.
Linder
Matts D
MD
Institute of Biomedicine/Anatomy, Haartmaninkatu 8, 00014 University of Helsinki, Finland.
Mäyränpää
Mikko I
MI
Peränen
Johan
J
Pietilä
Taija E
TE
Pietiäinen
Vilja M
VM
Uronen
Riikka-Liisa
RL
Olkkonen
Vesa M
VM
Kovanen
Petri T
PT
Ikonen
Elina
E
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000378:metabolism; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism*; D006801:Humans; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
C577836:ABCA1 protein, human; C505693:APOA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D034741:RNA, Small Interfering; D002784:Cholesterol; C082377:RAB8A protein, human; D020691:rab GTP-Binding Proteins