Bis(monoacylglycero)phosphate reduces oxysterol formation and apoptosis in macrophages exposed to oxidized LDL

Arnal-Levron, Maud; Chen, Yinan; Delton-Vandenbroucke, Isabelle; Luquain-Costaz, Céline

doi:10.1016/j.bcp.2013.03.017

Cited by 13 publications

(12 citation statements)

References 39 publications

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“…It is characterized by the disturbance of cholesterol homeostasis in plasma and vascular cells, especially in resident macrophages in the subendothelial space in relation with excessive oxidation of circulating LDL [1,2]. The transition from asymptomatic to symptomatic disease mainly depends on sudden atherosclerotic plaque rupture and the subsequent thrombosis [3].…”

Section: Introductionmentioning

confidence: 99%

STAT6 Upregulation Promotes M2 Macrophage Polarization to Suppress Atherosclerosis

Gong

Zhuo

2017

Med Sci Monit Basic Res

127

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BackgroundMacrophages are highly heterogeneous and plastic cells that are involved in all stages of atherogenesis. They can undergo polarization by shifting between M1 and M2 functional phenotypes. However, the role of macrophage polarization and the molecular mechanism in modulating atherosclerotic plaque stability remain incompletely understood. Our study investigated the role of STAT6 in regulating macrophage phenotypes to affect atherosclerotic plaque stability.Material/MethodsA murine atherosclerosis model with vulnerable plaques was induced with high-cholesterol diet and PCCP surgeries in ApoE−/− mice. Murine macrophages RAW264.7 treated with ox-LDL or IL-4 were used to simulate the in vitro process. pcDNA3.1(−)/STAT6-expressing vectors were transfected into RAW264.7 to evaluate its effect on cell polarization and the involved molecules.ResultsUnstable plaques presented significantly increased M1 markers (CD86 and iNOS) and less M2 markers (Arg-1 and TGF-β) than the stable plaques. Moreover, we found that STAT6 and p-STAT6 were greatly decreased in the vulnerable plaques and ox-LDL-induced macrophages, while their expression was elevated after IL-4 stimulation. The overexpression of STAT6 substantially reversed the ox-LDL-stimulated macrophage apoptosis and lipid accumulation. STAT6 upregulation promoted the differentiation of macrophage to M2 subtype as reflected by the increased expression of Arg-1 and TGF-β. Furthermore, we found that STAT6 overexpression activated the Wnt-β-catenin signaling by enhancing the translocation of β-catenin, while β-catenin suppression inhibited STAT6 overexpression-induced M2 polarization.ConclusionsSTAT6 facilitated atherosclerotic plaque stabilization by promoting the polarization of macrophages to M2 subtype and antagonizing ox-LDL-induced cell apoptosis and lipid deposition in a Wnt-β-catenin-dependent manner.

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Section: Introductionmentioning

confidence: 99%

STAT6 Upregulation Promotes M2 Macrophage Polarization to Suppress Atherosclerosis

Gong

Zhuo

2017

Med Sci Monit Basic Res

127

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“…33 However, both 25-hydroxycholesterol and 27-hydroxycholesterol were detected at very low levels in control cells and were not increased on LDL loading, not supporting their involvement in LXR activation. 34 Another potent LXR activator is 24(S),25-epoxycholesterol, a unique oxysterol in that it is produced through a shunt of the mevalonate pathway for cholesterol. Several studies have shown that inhibition of 24(S),25-epoxycholesterol synthesis is correlated with ABCA1 downregulation, whereas stimulation induced upregulation.…”

Section: Discussionmentioning

confidence: 99%

Bis(Monoacylglycero)Phosphate Accumulation in Macrophages Induces Intracellular Cholesterol Redistribution, Attenuates Liver-X Receptor/ATP-Binding Cassette Transporter A1/ATP-Binding Cassette Transporter G1 Pathway, and Impairs Cholesterol Efflux

Luquain-Costaz

Lefai

Arnal-Levron

et al. 2013

ATVB

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Objective— Endosomal signature phospholipid bis(monoacylglycero)phosphate (BMP) has been involved in the regulation of cellular cholesterol homeostasis. Accumulation of BMP is a hallmark of lipid storage disorders and was recently reported as a noticeable feature of oxidized low-density lipoprotein–laden macrophages. This study was designed to delineate the consequences of macrophage BMP accumulation on intracellular cholesterol distribution, metabolism, and efflux and to unravel the underlying molecular mechanisms. Approach and Results— We have developed an experimental design to specifically increase BMP content in RAW 264.7 macrophages. After BMP accumulation, cell cholesterol distribution was markedly altered, despite no change in low-density lipoprotein uptake and hydrolysis, cholesterol esterification, or total cell cholesterol content. The expression of cholesterol-regulated genes sterol regulatory element–binding protein 2 and hydroxymethylglutaryl-coenzyme A reductase was decreased by 40%, indicative of an increase of endoplasmic reticulum–associated cholesterol. Cholesterol delivery to plasma membrane was reduced as evidenced by the 20% decrease of efflux by cyclodextrin. Functionally, BMP accumulation reduced cholesterol efflux to both apolipoprotein A1 and high-density lipoprotein by 40% and correlated with a 40% decrease in mRNA contents of ATP-binding cassette transporter A1, ATP-binding cassette transporter G1, and liver-X receptor α and β. Foam cell formation induced by oxidized low-density lipoprotein exposure was exacerbated in BMP-enriched cells. Conclusions— The present work shows for the first time a strong functional link between BMP and cholesterol-regulating genes involved in both intracellular metabolism and efflux. We propose that accumulation of cellular BMP might contribute to the deregulation of cholesterol homeostasis in atheromatous macrophages.

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“…The bulk of oxysterols in oxLDL are oxidized at carbon 7, such as 7β-hydroxycholesterol (7β-HC) and 7-ketocholesterol (7-keto). These oxysterols are responsible for the ability of oxLDL to induce cellular oxidative stress and cytotoxicity, mainly via apoptosis [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

“…Another important effector of oxysterols is bis(monoacylglycero) phosphate (BMP), a phospholipid preferentially found in LE membranes. BMP participates in cholesterol metabolism/trafficking in macrophages and regulates cholesterol efflux to HDL [5,[14][15][16][17]. We recently showed that BMP exerts a protective action against the proapoptotic effect of oxLDL via a reduced production of intracellular oxysterols [5], but the underlying molecular mechanism remains to be characterized.…”

Section: Introductionmentioning

confidence: 99%

Bis(monoacylglycero)phosphate regulates oxysterol binding protein-related protein 11 dependent sterol trafficking

Arnal-Levron

Chen

Greimel

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Bis(Monoacylglycero) Phosphate (BMP) is a unique phospholipid localized in late endosomes, a critical cellular compartment in low density lipoprotein (LDL)-cholesterol metabolism. In previous work, we demonstrated the important role of BMP in the regulation of macrophage cholesterol homeostasis. BMP exerts a protective role against the pro-apoptotic effect of oxidized LDL (oxLDL) by reducing the production of deleterious oxysterols. As the intracellular sterol traffic in macrophages is in part regulated by oxysterol binding protein (OSBP) and OSBPrelated proteins (ORPs), we investigated the role of ORP11, localized at the Golgi-late endosomes interface, in the BMP-mediated protection from oxLDL/oxysterol cytotoxicity. Stably silencing of ORP11 in mouse RAW264.7 macrophages via a shRNA lentiviruses system had no effect on BMP production. However, ORP11 knockdown abrogated the protective action of BMP against oxLDL induced apoptosis. In oxLDL treated control cells, BMP enrichment was associated with reduced generation of 7-oxysterols, while these oxysterol species were abundant in the ORP11 knock-down cells. Of note, BMP enrichment in ORP11 knock-down cells was associated with a drastic increase in free cholesterol and linked to a decrease of cholesterol efflux. The expression of ATP-binding cassette-transporter G1 (ABCG1) was also reduced in the ORP11 knock-down cells. These observations demonstrate a cooperative function of OPR11 and BMP, in intracellular cholesterol trafficking in cultured macrophages. We suggest that BMP favors the egress of cholesterol from late endosomes via an ORP11-dependent mechanism, resulting in a reduced production of cytotoxic 7-oxysterols.

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Bis(monoacylglycero)phosphate reduces oxysterol formation and apoptosis in macrophages exposed to oxidized LDL

Cited by 13 publications

References 39 publications

STAT6 Upregulation Promotes M2 Macrophage Polarization to Suppress Atherosclerosis

STAT6 Upregulation Promotes M2 Macrophage Polarization to Suppress Atherosclerosis

Bis(Monoacylglycero)Phosphate Accumulation in Macrophages Induces Intracellular Cholesterol Redistribution, Attenuates Liver-X Receptor/ATP-Binding Cassette Transporter A1/ATP-Binding Cassette Transporter G1 Pathway, and Impairs Cholesterol Efflux

Bis(monoacylglycero)phosphate regulates oxysterol binding protein-related protein 11 dependent sterol trafficking

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