This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 29/6/883    most recent ATVBAHA.108.179481v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Linder, M. D. Articles by Ikonen, E. PubMed PubMed Citation Articles by Linder, M. D. Articles by Ikonen, E.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:883.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Rab8 Regulates ABCA1 Cell Surface Expression and Facilitates Cholesterol Efflux in Primary Human Macrophages

Matts D. Linder; Mikko I. Mäyränpää; Johan Peränen; Taija E. Pietilä; Vilja M. Pietiäinen; Riikka-Liisa Uronen; Vesa M. Olkkonen; Petri T. Kovanen; Elina Ikonen

From the Institute of Biomedicine/Anatomy (M.D.L., V.M.P., R.-L.U., E.I.), University of Helsinki; Wihuri Research Institute (M.I.M., P.T.K.), Helsinki; the Department of Forensic Medicine (M.I.M.), University of Helsinki; Institute of Biotechnology (J.P.), University of Helsinki; and National Institute for Health and Welfare (T.E.P., V.M.O.), Helsinki, Finland.

Correspondence to Elina Ikonen, Institute of Biomedicine/Anatomy, Haartmaninkatu 8, 00014 University of Helsinki, Finland. E-mail elina.ikonen{at}helsinki.fi

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.

Methods and 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 β1 integrin and transferrin receptor containing recycling organelles.

Conclusion— Rab8 reduces foam cell formation by facilitating ABCA1 surface expression and stimulating endosomal cholesterol efflux to apoA-I in primary human macrophages.

Key Words: Rab GTPase • foam cell • apolipoprotein A-I • ATP-binding cassette transporter