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

Abstract

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.

Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

“…In addition, storage of sphingosine causes a loss in lysosomal calcium regulation which slows the rate at which autophagic vacuoles are processed by LE/Lys (Lloyd-Evans and Platt, 2010). Mechanism DIPL results in changes in lysosomal function (Kobayashi et al, 1998;Tengstrand et al, 2010) and cholesterol status (Chevallier et al, 2008;Luquain-Costaz et al, 2013;Xu et al, 2008) that are observed in NPC disease. CADs inhibit the activities of phospholipases A and C and lysosomal enzymes that are deficient in sphingolipidoses (i.e., aSMase (Niemann-Pick), acid ceramidase (Farber), acid lipase (Wolman)) (Kornhuber et al, 2010).…”

Schistosoma mansoniinfection reprograms the metabolic potential of the myeloid lineage in a mouse model of metabolic syndrome

“…When we examine these features individually, we can see a differential response to infection for males and females (for instance, PG 18:1_18:2, a glycerophospholipid) represented in Supplemental Figure 2C). Seven of the 20 molecular features identified by machine learning are BMP (Bis(monoacylglycerol)phosphate) species, which have been implicated in glycosphingolipid degradation and cholesterol transport [54, 55]. These data further support the hypothesis that S. mansoni infection differentially modulates the metabolism of myeloid cells from male and female animals, and that this modulation revolves around decreased cholesterol storage and fatty acid synthesis in males and increased cholesterol storage and fatty acid synthesis in females.…”

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

“…2B). Additionally, ORP11 labelling also colocalized with BMP (M2 = 0.91 ± 0.05), known to be an endosomal resident in RAW264.7 macrophages and representing a typical punctated perinuclear pattern [17], consistent with a possible cooperation between these two factors involved in sterol trafficking.…”

“…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.…”