Linder Matts D, Mäyränpää Mikko I, Peränen Johan, Pietilä Taija E, Pietiäinen Vilja M, Uronen Riikka-Liisa, Olkkonen Vesa M, Kovanen Petri T, Ikonen Elina
Institute of Biomedicine/Anatomy, Haartmaninkatu 8, 00014 University of Helsinki, Finland.
Arterioscler Thromb Vasc Biol. 2009 Jun;29(6):883-8. doi: 10.1161/ATVBAHA.108.179481. Epub 2009 Mar 19.
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.
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.
Rab8 reduces foam cell formation by facilitating ABCA1 surface expression and stimulating endosomal cholesterol efflux to apoA-I in primary human macrophages.
三磷酸腺苷结合盒转运体A1（ABCA1）被认为在质膜上使载脂蛋白A-I（apoA-I）脂化，内体胆固醇作为底物参与其中。ABCA1向细胞表面转运的机制尚不完全清楚。我们已经证明，Rab8调节人成纤维细胞内体胆固醇向apoA-I的转运。在此，我们研究了Rab8在原代人巨噬细胞的ABCA1质膜表达和胆固醇转运中是否发挥作用。
我们发现Rab8在人动脉粥样硬化病变巨噬细胞中大量表达，并且在体外巨噬细胞脂质加载时上调。Rab8的腺病毒过表达增加了ABCA1蛋白水平，并减少了与apoA-I孵育的巨噬细胞泡沫细胞中的胆固醇沉积。Rab8的缺失降低了质膜上ABCA1的比例，并抑制了脂蛋白衍生的内体胆固醇向apoA-I的流出。在Rab8缺失的细胞中，ABCA1-绿色荧光蛋白定位于含有β1整合素和转铁蛋白受体的再循环细胞器中。
Rab8通过促进ABCA1在细胞表面的表达并刺激原代人巨噬细胞内体胆固醇向apoA-I的流出，减少泡沫细胞的形成。
