Is ABCA1 a lipid transfer protein?

Phillips, Michael C.

doi:10.1194/jlr.r082313

Cited by 127 publications

(134 citation statements)

References 174 publications

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“…Cholesterol efflux represents a major mechanism of macrophage cholesterol removal and recycling. ABCA1 and ABCG1 are major macrophage cholesterol transporters involved in cholesterol efflux, both are tightly regulated through TFs and coregulators (1,4,18,25). In this study, we discover a novel mechanism of endotoxin-induced Abca1 expression and cholesterol efflux by the coregulator GPS2 which seems conserved in both mouse and human macrophages.…”

Section: Discussionmentioning

confidence: 80%

“…Failure of cholesterol removal from macrophages induces foam cell conversion, which promotes the formation of atherogenic lesions by boosting local inflammatory cytokine secretion and by recruiting immune cells (2,3). Macrophage cholesterol efflux is mediated mainly by the cholesterol transporters ATP-binding cassette transporter (ABC)-A1 and ABCG1 (4). The expression of these transporters is tightly regulated by transcription factors (TFs), such as liver X receptors (LXRs) and peroxisome proliferator activated receptor g (PPARg) (5)(6)(7)(8); by coregulators, such as nuclear receptor corepressor 1 (NCOR1) and nuclear receptor coactivator 5 (NCOA5) (9,10); and by long, noncoding RNAs, such as macrophage-expressed LXR-induced sequence (MeXis), that specifically regulate LXR-dependent Abca1 expression (11).…”

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confidence: 99%

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G protein pathway suppressor 2 (GPS2) links inflammation and cholesterol efflux by controlling lipopolysaccharide‐induced ATP‐binding cassette transporter A1 expression in macrophages

et al. 2018

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Macrophages play important roles in linking alterations of cholesterol metabolism and inflammation to the development of atherosclerosis. Previous studies have identified several positive and negative crosstalk mechanisms that connect cholesterol efflux and inflammation at the transcriptional level. Of particular relevance is that the expression of ATP‐binding cassette transporter A1 (Abca1), a main regulator of cholesterol efflux, can be induced by oxysterol receptor LXR agonists but also by bacterial endotoxins, such as LPS, that activate TLR4 signaling. However, the extent to which these pathways influence each other has remained incompletely understood. We investigated the possible role of the transcriptional coregulator G protein pathway suppressor 2 (GPS2) in LPS‐induced Abca1 expression and cholesterol efflux in mouse and human macrophages. To activate Abca1, GPS2 cooperates with the LPS‐inducible NF‐κB subunit p65, but not with LXRs nor with corepressor complex subunits that otherwise cooperate with GPS2 to repress proinflammatory gene expression. Overall, our work identifies a regulatory chromatin component of crosstalk mechanisms between cholesterol efflux and inflammation that specifically affects ABCA1. Because GPS2 expression is down‐regulated in some humans with obese and type 2 diabetes, the macrophage GPS‐2/ABC‐A1 pathway could be altered and contribute to atherogenesis.—Huang, Z., Liang, N., Damdimopoulos, A., Fan, R., Treuter, E. G protein pathway suppressor 2 (GPS2) links inflammation and cholesterol efflux by controlling lipopolysaccharide‐induced ATP‐binding cassette transporter A1 expression in macrophages. FASEB J. 33, 1631–1643 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 80%

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confidence: 99%

G protein pathway suppressor 2 (GPS2) links inflammation and cholesterol efflux by controlling lipopolysaccharide‐induced ATP‐binding cassette transporter A1 expression in macrophages

et al. 2018

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“…Emerging evidence has pointed to ATP-binding cassette (ABC) transporters as a membrane protein transporter for lipids, that mediate the bidirectional transfer of lipids inside and outside cells. Indeed, ABC transporter A1 (ABCA1) mediates the transfer of cellular phospholipid and free cholesterol [27]. The present in situ PKCα assay clearly demonstrates that extracellularly applied DOPE inhibited activated PKCα in cells.…”

Section: Discussionmentioning

confidence: 86%

Dioleoylphosphoethanolamine Retains Cell Surface GLUT4 by Inhibiting PKCα-Driven Internalization

Nishizaki¹

2018

Cell Physiol Biochem

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Background/Aims: Phosphatidylethanolamine, a component of the plasma membrane, regulates diverse cellular processes. The present study investigated the role of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in the trafficking of the glucose transporter GLUT4 and the glucose homeostasis. Methods: Monitoring of GLUT4 trafficking, GLUT4 internalization assay, and glucose uptake assay were carried out using differentiated 3T3-L1-GLUT4myc adipocytes. Akt1/2 and PKC isozymes were knocked-down by transfecting each siRNA. Cell-free PKC assay and in situ PKCα assay with a FRET probe were carried out. Oral glucose tolerance test (OGTT) was performed using BKS.Cg-+Lep^db/+Leb^db/Jcl mice, an animal model of type 2 diabetes mellitus (DM). Results: DOPE increased cell surface localization of the glucose transporter GLUT4 in differentiated 3T3-L1-GLUT4myc adipocytes, regardless of Akt activation. Likewise, PKCα deficiency increased cell surface localization of GLUT4, that occludes the effect of DOPE. DOPE clearly suppressed phorbol 12-myristate 13-acetate-induced PKCα activation in the cell-free and in situ PKC assay. DOPE and PKCα deficiency cancelled endocytic internalization of GLUT4 localized on the plasma membrane after insulin stimulation. DOPE significantly enhanced glucose uptake into cells. A similar effect was obtained by knocking-down PKCα, that occludes the effect of DOPE. In OGTT, oral administration with DOPE effectively restricted an increase in the blood glucose levels after glucose loading in type 2 DM model mice. Conclusion: The results of the present study show that DOPE retains cell surface GLUT4 by suppressing PKCα-driven endocytic internalization of GLUT4, to enhance glucose uptake into cells and restrict an increase in the blood glucose levels after glucose loading in type 2 DM.

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“…Furthermore, it has been suggested that the ABCG5/ABCG8 complex performs such a function in hepatocyte canaliculi . However, there is no direct evidence that ABCA1 or ABCG1 actually flips cholesterol . A major concern with this hypothesis is that cholesterol diffuses rapidly across the bilayer, so that the cells would have to work hard to maintain a 10‐fold gradient against rapid passive back‐flux.…”

Section: Evidence For Excess Cholesterol In the Outer Leafletmentioning

confidence: 99%

“…67 However, there is no direct evidence that ABCA1 or ABCG1 actually flips cholesterol. [68][69][70] A major concern with this hypothesis is that cholesterol diffuses rapidly across the bilayer, so that the cells would have to work hard to maintain a 10-fold gradient against rapid passive back-flux. A rough calculation: Assume that cholesterol diffuses across plasma membranes with a leisurely time constant of 1 second.…”

Section: Tagged Toxinsmentioning

confidence: 99%

Transverse distribution of plasma membrane bilayer cholesterol: Picking sides

Steck

Lange

2018

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The transverse asymmetry (sidedness) of phospholipids in plasma membrane bilayers is well characterized, distinctive, actively maintained and functionally important. In contrast, numerous studies using a variety of techniques have concluded that plasma membrane bilayer cholesterol is either mostly in the outer leaflet or the inner leaflet or is fairly evenly distributed. Sterols might simply partition according to their differing affinities for the asymmetrically disposed phospholipids, but some studies have proposed that it is actively transported to the outer leaflet. Other work suggests that the sterol is enriched in the inner leaflet, driven by either positive interactions with the phosphatidylethanolamine on that side or by its exclusion from the outer leaflet by the long chain sphingomyelin molecules therein. This uncertainty raises three questions: is plasma membrane cholesterol sidedness fixed in a given cell or cell type; is it generally the same among mammalian species; and does it serve specific physiological functions? This review grapples with these issues.

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Is ABCA1 a lipid transfer protein?

Cited by 127 publications

References 174 publications

G protein pathway suppressor 2 (GPS2) links inflammation and cholesterol efflux by controlling lipopolysaccharide‐induced ATP‐binding cassette transporter A1 expression in macrophages

G protein pathway suppressor 2 (GPS2) links inflammation and cholesterol efflux by controlling lipopolysaccharide‐induced ATP‐binding cassette transporter A1 expression in macrophages

Dioleoylphosphoethanolamine Retains Cell Surface GLUT4 by Inhibiting PKCα-Driven Internalization

Transverse distribution of plasma membrane bilayer cholesterol: Picking sides

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