AMPK activates LXRα and ABCA1 expression in human macrophages.
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.
['Kemmerer|Marina|M|', 'Wittig|Ilka|I|', 'Richter|Florian|F|', 'Brüne|Bernhard|B|', 'Namgaladze|Dmitry|D|']
D055372:AMP-Activated Protein Kinases D064286:ATP Binding Cassette Transporter 1 D001692:Biological Transport D002784:Cholesterol D004789:Enzyme Activation D048049:Extracellular Signal-Regulated MAP Kinases D005786:Gene Expression Regulation D056945:Hep G2 Cells D006655:Histone Deacetylases D006801:Humans D000071518:Liver X Receptors D008264:Macrophages D011401:Promoter Regions, Genetic D012097:Repressor Proteins D058570:TOR Serine-Threonine Kinases
Macrophages Cholesterol Transcription AMP‐activated protein kinase (AMPK) Gene expression Nuclear receptors