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.

Céline Luquain-Costaz; Etienne Lefai; Maud Arnal-Levron; Daria Markina; Shota Sakaï; Vanessa Euthine; Asami Makino; Michel Guichardant; Shizuya Yamashita; Toshihide Kobayashi; Michel Lagarde; Philippe Moulin; Isabelle Delton-Vandenbroucke

doi:10.1161/ATVBAHA.113.301857

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.: BMP and LXRs/ABCs pathway in macrophages

Céline Luquain-Costaz ¹ Etienne Lefai ¹ Maud Arnal-Levron ¹ Daria Markina ¹ Shota Sakaï ² Vanessa Euthine ¹ Asami Makino ² Michel Guichardant ¹ Shizuya Yamashita ³ Toshihide Kobayashi ² Michel Lagarde ¹ Philippe Moulin ¹ Isabelle Delton-Vandenbroucke ^{1, *}

* Auteur correspondant

1 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition

2 Lipid Biology Laboratory

3 Department of Cardiovascular Medicine

Department of Cardiovascular Medicine

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.

Keywords : ATP-binding cassette transporters atherosclerosis endosomes lipoproteins oxysterol receptors

Type de document :

Article dans une revue

Arteriosclerosis, Thrombosis, and Vascular Biology, American Heart Association, 2013, 33 (8), pp.1803-11. 〈10.1161/ATVBAHA.113.301857〉

Domaine :

Sciences du Vivant [q-bio] / Alimentation et Nutrition

Liste complète des métadonnées

Littérature citée [37 références] Voir Masquer Télécharger

http://www.hal.inserm.fr/inserm-00844488
Contributeur : Evelyne Vericel <>
Soumis le : samedi 30 novembre 2013 - 14:00:15
Dernière modification le : lundi 30 juillet 2018 - 11:02:01
Document(s) archivé(s) le : lundi 3 mars 2014 - 13:55:41

luquain-costaz_version_HAL.pdf

Fichiers produits par l'(les) auteur(s)

inserm-00844488_edited.pdf Fichiers produits par l'(les) auteur(s)

Céline Luquain-Costaz, Etienne Lefai, Maud Arnal-Levron, Daria Markina, Shota Sakaï, et al.. 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.: BMP and LXRs/ABCs pathway in macrophages. Arteriosclerosis, Thrombosis, and Vascular Biology, American Heart Association, 2013, 33 (8), pp.1803-11. 〈10.1161/ATVBAHA.113.301857〉. 〈inserm-00844488〉

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.: BMP and LXRs/ABCs pathway in macrophages

Fichiers

Identifiants

Collections

Citation

Exporter

Métriques

484

670

Contact

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.: BMP and LXRs/ABCs pathway in macrophages

Fichiers

Identifiants

Collections

Citation

Exporter

Partager

Métriques

484

670

Contact