title: Phospholipase A(2)-modified low-density lipoprotein activates liver X receptor in human macrophages.
abstract: Macrophages respond to cholesterol accumulation by increasing cholesterol efflux, which is mediated by activation of the nuclear liver X receptor (LXR) and ATP binding cassette (ABC) transporters. In the present study, we investigated whether foam cell formation induced by phospholipase A(2)-modified low-density lipoprotein (PLA-LDL) influences LXR activity and cholesterol efflux in primary human monocyte-derived macrophages (MDMs). Macrophages were treated with PLA-LDL and expression of the LXR target genes ABCA1 and ABCG1 was analyzed by quantitative PCR and western blot. PLA-LDL time-dependently up-regulated ABCA1 and ABCG1 mRNA and protein. Removal of non-esterified fatty acids from PLA-LDL particles did not influence the induction of ABC transporters. A role of LXR in PLA-LDL-stimulated ABCG1 expression was verified by LXR-knockdown and luciferase reporter assays using a construct containing a LXR response element from the ABCG1 gene. Functionally, cholesterol efflux to apolipoprotein A-I and high-density lipoprotein was higher in PLA-LDL treated cells compared to controls. Together, these results demonstrate that in primary human MDMs PLA-LDL induces ABC transporter expression via LXR activation. A concomitantly increased cholesterol efflux may prevent excessive cholesterol accumulation and thus, attenuate foam cell formation.
authors.affiliation: Faculty of Medicine, Institute of Biochemistry I/ZAFES, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Morbitzer
authors.forename: Dmitry
authors.initials: D
authors.lastname: Namgaladze
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
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; D016632:Apolipoprotein A-I / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000502:physiology; D000071518:Liver X Receptors; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D054467:Phospholipases A2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; C505693:APOA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D002784:Cholesterol; D049410:Luciferases, Renilla; D054467:Phospholipases A2