title: AMPK activates LXRα and ABCA1 expression in human macrophages.
abstract: ATP-binding cassette transporter A1 (ABCA1) is a key modulator of macrophage cholesterol homeostasis. We studied the impact of AMP-activated protein kinase (AMPK) on ABCA1 expression in primary human and THP-1 macrophages. Pharmacological or genetic activation of AMPK increased mRNA and protein expression of ABCA1 and its transcriptional activator liver X receptor (LXR) α, resulting in increased cholesterol efflux to apolipoprotein AI-containing medium. On the other side, an AMPK knockdown decreased ABCA1 and LXRα mRNA and protein. Silencing LXRα, but not LXRβ, attenuated ABCA1 expression after AMPK activation, and luciferase reporter as well as chromatin immunoprecipitation analyses showed the binding of LXRα to the LXR responsive element in the ABCA1 promoter. Inhibition of extracellular-signal regulated kinase and mechanistic target of rapamycin signalling increased ABCA1 expression, at the same time making it unresponsive to AMPK activation. Considering other potential regulators of ABCA1 expression, we excluded histone deacetylase HDAC9 and FOXO3 involvement in mediating AMPK effects on ABCA1. Our data link AMPK activation to an increased cholesterol efflux capacity of macrophages, suggesting an atheroprotective effect of macrophage AMPK.
authors.affiliation: Goethe-University Frankfurt, Faculty of Medicine, Institute of Biochemistry I, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Kemmerer
authors.affiliation: Goethe-University Frankfurt, Functional Proteomics, SFB 815 Core Unit, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Wittig
authors.affiliation: Goethe-University Frankfurt, Functional Proteomics, SFB 815 Core Unit, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Richter
authors.affiliation: Goethe-University Frankfurt, Faculty of Medicine, Institute of Biochemistry I, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
authors.affiliation: Goethe-University Frankfurt, Faculty of Medicine, Institute of Biochemistry I, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. Electronic address: namgaladze@biochem.uni-frankfurt.de.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Namgaladze
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics*; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D000071518:Liver X Receptors / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000071518:Liver X Receptors; D012097:Repressor Proteins; D002784:Cholesterol; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases; C486544:HDAC9 protein, human; D006655:Histone Deacetylases
keywords: AMP‐activated protein kinase (AMPK); Cholesterol; Gene expression; Macrophages; Nuclear receptors; Transcription