Cholesterol efflux is LXRα isoform-dependent in human macrophages.

Zhi Yuan Song,A Zhi Sha Ma,Qian Zhang

doi:10.1186/1471-2261-14-80

Abstract

BackgroundThe nuclear receptor liver X receptor (LXR) has two isoforms: LXRα and LXRβ. LXR activation promotes cholesterol efflux in macrophages, but the relative importance of each LXR isoform in mediating cholesterol efflux remains elusive.MethodsWe evaluated the ability of different doses of LXRs agonist T0901317 to affect cholesterol efflux in human macrophages and its relationship with mRNA and protein levels of several well-characterized proteins involved in cholesterol efflux, including ABCA1, ABCG1, SR-BI, LXRβ and LXRα, using quantitative real-time PCR, Western blotting, and siRNA techniques.ResultsHere we show that LXRα rather than LXRβ sustains baseline cholesterol efflux in human blood-derived macrophages. Treatment of human macrophages with a non-isoform-specific LXR agonist T0901317 substantially increased HDL- and apoA-I-mediated cholesterol efflux, which was associated with increased mRNA and protein expression levels of ABCA1, ABCG1, SR-BI, LXRα and LXRβ. The siRNA- mediated silencing of LXRα, but not LXRβ significantly reduced the protein levels of ABCA1,ABCG1, and SR-BI as wellas HDL- and ApoA1-mediated cholesterol in human macrophages.ConclusionsThese findings imply that LXRα- rather than LXRβ- specific agonists may promote reverse cholesterol transport in humans.

Highlights

The nuclear receptor liver X receptor (LXR) has two isoforms: LXRα and LXRβ
We demonstrate that the baseline cholesterol efflux in human blood-derived macrophages depends on LXRα, but not LXRβ, implying a potential role of LXRαspecific activation in enhancing reverse cholesterol transport in humans
LXRs agonist T0901317 enhances cholesterol efflux in human macrophages To determine if LXRs agonist T0901317 promotes cholesterol efflux in human blood-derived macrophages, we measured high density lipoproteins (HDLs)- and apoAI-mediated cholesterol efflux in these macrophages

Summary

Introduction

The nuclear receptor liver X receptor (LXR) has two isoforms: LXRα and LXRβ. LXR activation promotes cholesterol efflux in macrophages, but the relative importance of each LXR isoform in mediating cholesterol efflux remains elusive. Macrophage cholesterol efflux is predominantly mediated by ATP-binding cassette (ABC) transporters A1 (ABCA1), ABCG1, and scavenger receptor class B type I (SR-BI) [3]. It is the initial step of reverse cholesterol transport (RCT), a process that removes excess cholesterol from peripheral tissues/cells including macrophages to circulating high density lipoproteins (HDLs) for fecal disposal via the hepatobiliary route [4]. Liver X receptors (LXRs) are nuclear receptors that function as cholesterol sensors and regulate transcription of a set of mammals, LXRα is abundantly expressed in the liver, adipose tissue, small intestine, kidneys and macrophages, whereas the LXRβ isoform is ubiquitously expressed [10]. The relative importance of each LXR isoform in mediating cholesterol efflux in human macrophages remains elusive. We demonstrate that the baseline cholesterol efflux in human blood-derived macrophages depends on LXRα, but not LXRβ, implying a potential role of LXRαspecific activation in enhancing reverse cholesterol transport in humans

Methods

Results

Conclusion