title: 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.
  
  
  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.
authors.affiliation: Université de Lyon, UMR 1060 Inserm, CarMeN, Institut National des Sciences Appliquées-Lyon, Villeurbanne, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Luquain-Costaz
authors.forename: Etienne
authors.initials: E
authors.lastname: Lefai
authors.forename: Maud
authors.initials: M
authors.lastname: Arnal-Levron
authors.forename: Daria
authors.initials: D
authors.lastname: Markina
authors.forename: Shota
authors.initials: S
authors.lastname: Sakaï
authors.forename: Vanessa
authors.initials: V
authors.lastname: Euthine
authors.forename: Asami
authors.initials: A
authors.lastname: Makino
authors.forename: Michel
authors.initials: M
authors.lastname: Guichardant
authors.forename: Shizuya
authors.initials: S
authors.lastname: Yamashita
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Michel
authors.initials: M
authors.lastname: Lagarde
authors.forename: Philippe
authors.initials: P
authors.lastname: Moulin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Delton-Vandenbroucke
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D008078:Cholesterol, LDL / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D000071518:Liver X Receptors; D008246:Lysophospholipids / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D050178:Monoglycerides / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000378:metabolism
chemical_list: C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D008078:Cholesterol, LDL; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D008246:Lysophospholipids; D050178:Monoglycerides; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; C012786:bis(monoacylglyceryl)phosphate; C099252:oxidized low density lipoprotein
keywords: ATP-binding cassette transporters; atherosclerosis; endosomes; lipoproteins