Atherosclerosis is characterized by the presence of cholesterol-laden macrophages (foam cells) within the arterial wall [
1,
2]. The formation of foam cells is a result of disrupted balance between cholesterol uptake and efflux in macrophages. 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 genes associated with cholesterol absorption, transport, efflux and excretion, thus playing a pivotal role in cholesterol homeostasis in vivo [
5]. There are two LXR isoforms, LXRα and LXRβ. Each of them forms a heterodimer with a retinoid X receptor (RXR) to activate target gene expression by 3 binding to LXR response elements (LXREs) located in the promoter 3 regions of the target genes [
6]. LXRα and LXRβ are similar in structure, ligand-binding domains (LBDs), and DNA-binding domains (DBDs), but their nuclear retention and localization as well as functions display some differences [
7]. The two isoforms may have evolved from one ancestor. Pufferfish has only one LXRα, which is more closely related to mammalian LXR genes by sequence similarity, yet the pattern of tissue expression more closely resembles mammalian LXRβ genes in its ubiquity of expression [
8]. The sequence data suggests that the two LXR isoforms are likely duplicated from a single ancestor LXR gene, and this duplication is concurrent with the evolution of mammals [
9]. In mammals, LXRα is abundantly expressed in the liver, adipose tissue, small intestine, kidneys and macrophages, whereas the LXRβ isoform is ubiquitously expressed [
10]. T0901317 is a general agonist for both LXR isoforms [
11]. It has been shown that the activation of LXRs by T0901317 facilitates cholesterol efflux in macrophages and inhibits atherosclerosis in animal models [
12,
13]. However, the relative importance of each LXR isoform in mediating cholesterol efflux in human macrophages remains elusive. In this study, we demonstrate that the baseline cholesterol efflux in human blood-derived macrophages depends on LXRα, but not LXRβ, implying a potential role of LXRα- specific activation in enhancing reverse cholesterol transport in humans.