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.

Keywords: AMP‐activated protein kinase (AMPK); Cholesterol; Gene expression; Macrophages; Nuclear receptors; Transcription.