Anti-bis(monoacylglycero)phosphate antibody accumulates acetylated LDL-derived cholesterol in cultured macrophages

Delton-Vandenbroucke, Isabelle; Bouvier, J B; Makino, Asami; Besson, Nelly; Pageaux, Jean‐François; Lagarde, Michel; Kobayashi, Toshihide

doi:10.1194/jlr.m600266-jlr200

Cited by 32 publications

(30 citation statements)

References 35 publications

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“…This indicates that BMP synthesized from exogenous PG is specifically located in late endosomes, similar to endogenous BMP (1,3). We may then assume that supplementation of RAW macrophages with 18:1/18:1-PG increases BMP content without altering its stereoconfiguration and cellular location, providing an alternative approach to the anti-BMP antibody or drugs such as D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (8,12) to investigate the functions of BMP in cellular models.…”

Section: Discussionmentioning

confidence: 99%

“…BMP is involved in the formation of the multivesicular membrane organization of late endosomes (4,5). It has been suggested that BMP participates in the trafficking of lipids and proteins, particularly cholesterol, through late endosomes (6)(7)(8). Recent studies have indicated that the ability of the endosomal Niemann-Pick C2 protein to transfer cholesterol to PL vesicles is increased by the presence of BMP (9,10).…”

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confidence: 99%

“…Of note, it has been reported that membranes enriched with DHA-containing PLs exclude cholesterol (24). We have been particularly interested in the role of BMP in the regulation of cholesterol homeostasis in macrophages (8), and DHA content of BMP might be important in this respect.…”

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confidence: 99%

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Selective decrease of bis(monoacylglycero)phosphate content in macrophages by high supplementation with docosahexaenoic acid

Bouvier

Berry

Hullin-Matsuda

et al. 2009

Journal of Lipid Research

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Bis(monoacylglycero)phosphate (BMP) is a unique phospholipid (PL) preferentially found in late endosomal membranes, where it forms specialized lipid domains. Recently, using cultured macrophages treated with anti-BMP antibody, we showed that BMP-rich domains are involved in cholesterol homeostasis. We had previously stressed the high propensity of BMP to accumulate docosahexaenoic acid (DHA), compared with other PUFAs. Because phosphatidylglycerol (PG) was reported as a precursor for BMP synthesis in RAW macrophages, we examined the effects of PG supplementation on both FA composition and amount of BMP in this cell line. Supplementation with dioleoyl-PG (18:1/18:1-PG) induced BMP accumulation, together with an increase of oleate proportion. Supplementation with high concentrations of didocosahexaenoyl-PG (22:6/22:6-PG) led to a marked enrichment of DHA in BMP, resulting in the formation of diDHA molecular species. However, the amount of BMP was selectively decreased. Similar effects were observed after supplementation with high concentrations of nonesterified DHA. Addition of vitamin E prevented the decrease of BMP and further increased its DHA content. Supplementation with 22:6/22:6-PG promoted BMP accumulation with an enhanced proportion of 22:6/22:6-BMP. DHA-rich BMP was significantly degraded after cell exposure to oxidant conditions, in contrast to oleic acid-rich BMP, which was not affected. Using a cell-free system, we showed that 22:6/22:6-BMP is highly oxidizable and partially protects cholesterol oxidation, compared with 18:1/18:1-BMP. Our data suggest that high DHA content in BMP led to specific degradation of this PL, possibly through the diDHA molecular species, which is very prone to peroxidation and, as such, a potential antioxidant in its immediate

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Selective decrease of bis(monoacylglycero)phosphate content in macrophages by high supplementation with docosahexaenoic acid

Bouvier

Berry

Hullin-Matsuda

et al. 2009

Journal of Lipid Research

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“…It was then shown to be enriched in lysosomes of the rat liver (2) and in alveolar macrophages (3) and reported to accumulate in lipid storage diseases and drug-induced lipidosis (4)(5)(6). Recently, it was demonstrated that this peculiar phospholipid is selectively enriched in the internal membranes of late endosomes (LEs), where it participates in the trafficking of proteins and lipids, particularly cholesterol, through this organelle (6)(7)(8). In addition, BMP is involved in the formation of the multivesicular membranes characteristic of the LE (9)(10)(11)(12)(13)(14).…”

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confidence: 99%

De novo biosynthesis of the late endosome lipid, bis(monoacylglycero)phosphate

Hullin-Matsuda

Kawasaki

Delton-Vandenbroucke

et al. 2007

Journal of Lipid Research

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Bis(monoacylglycero)phosphate (BMP) is a unique lipid enriched in the late endosomes participating in the trafficking of lipids and proteins through this organelle. The de novo biosynthesis of BMP has not been clearly demonstrated. We investigated whether phosphatidylglycerol (PG) and cardiolipin (CL) could serve as precursors of de novo BMP synthesis using two different cellular models: CHO cells deficient in phosphatidylglycerophosphate (PGP) synthase, the enzyme responsible for the first step of PG synthesis; and human lymphoblasts from patients with Barth syndrome (BTHS), characterized by mutations in tafazzin, an enzyme implicated in the deacylation-reacylation cycle of CL. The biosynthesis of both PG and BMP was reduced significantly in the PGP synthase-deficient CHO mutants. Furthermore, overexpression of PGP synthase in the deficient mutants induced an increase of BMP biosynthesis. In contrast to CHO mutants, BMP biosynthesis and its fatty acid composition were not altered in BTHS lymphoblasts. Our results thus suggest that in mammalian cells, PG, but not CL, is a precursor of the de novo biosynthesis of BMP. Despite the decrease of de novo synthesis, the cellular content of BMP remained unchanged in CHO mutants, suggesting that other pathway(s) than de novo biosynthesis are also used for BMP synthesis.

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“…7 Our studies in both murine and human macrophages showed that endosomal accumulation of anti-BMP antibody altered cholesterol distribution in relation to reduced cholesterol efflux to HDL. 8 Most human and animal cells or tissues contain relatively low amounts of BMP, not exceeding 1% to 2% of total phospholipids. However, the level of BMP was shown to dramatically increase in certain inherited lysosomal storage disorders, a group of diseases characterized by endolysosomal lipidosis, such as Niemann-Pick (NP) and Gaucher diseases.…”

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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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Anti-bis(monoacylglycero)phosphate antibody accumulates acetylated LDL-derived cholesterol in cultured macrophages

Cited by 32 publications

References 35 publications

Selective decrease of bis(monoacylglycero)phosphate content in macrophages by high supplementation with docosahexaenoic acid

Selective decrease of bis(monoacylglycero)phosphate content in macrophages by high supplementation with docosahexaenoic acid

De novo biosynthesis of the late endosome lipid, bis(monoacylglycero)phosphate

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

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