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  • The Liver X Receptor and LXRs NR

    2020-10-12

    The Liver X Receptor-α and -β (LXRs, NR1H3 and NR1H2, respectively) are members of the nuclear receptor superfamily that play a central role in controlling cholesterol homeostasis [9], [10]. In macrophages, LXRs can decrease the cellular sterol burden by inducing expression of the cholesterol efflux transporters Abca1 and Abcg1[11], [12], and by limiting uptake of LDL-derived cholesterol due to induction of Idol, an E3 ubiquitin ligase that promotes lysosomal degradation of the LDLR [13]. Despite the crucial role of LXRs in cholesterol homeostasis, their effect on cellular cholesterol storage is not well understood. Through transcriptional profiling, we have identified that Enolase is subject to LXR-dependent regulation [14]. Here, we show that Enolase transcript and protein abundance are reduced by LXRs in macrophages and intestine and discuss the impact this may have on mobilization of cholesterol towards efflux pathways.
    Materials and methods
    Results
    Discussion We report herein the regulation of Enolase by LXRs. The major finding of this study is that activated LXRs decrease Eno1 expression and corresponding protein levels in murine macrophages and in vivo in a tissue-specific and LXR-dependent manner. Despite being an important metabolic enzyme the regulation of Eno1 expression is poorly understood. Recently, Cai et al. reported that Estrogen-Related Receptors (ERRs) α, β, and γ (NR3B1, 2 and 3, respectively) can bind and drive transcriptional activity of the Eno1 promoter in cooperation with hypoxia-inducible factors under hypoxic conditions [19]. Expression of ENO1 is also highly responsive to proinflammatory signals such as IL- 1β, IL-6, PGE2, or TNF-α in peripheral blood mononuclear TIC10 receptor [20]. These cytokines, largely acting through the NF-κB pathway, increase expression of ENO1 as part of the inflammatory program. Our finding that LXRs are potent repressors of Eno1 expression further illustrates the complex regulation of this enzyme. An important question that emerges from our study relates to the mechanism underlying repression of Eno1 expression by LXRs. LXR binding has been observed by ChIP-seq analysis in the vicinity of the ENO1 gene in human macrophages [21]. However, careful in silico analyses of both human and mouse promoters failed to reveal potential bindings sites (not shown). Alternatively, it is well established that LXR are potent anti-inflammatory factors in macrophages, largely due to their ability to trans-repress inflammatory gene signaling [22], [23]. Accordingly, ligand activated LXRs inhibit expression of NF-κB-responsive genes such as COX2, iNOS and MMP-9 during the inflammatory response [24]. Given that ENO1 gene expression is also enhanced by NF-κB signaling we postulate that repression of Eno1 by LXRs may follow a similar mechanism, an hypothesis that warrants future studies. The question is still open in the context of human macrophages. Preliminary data lead us to confirm that ENO1 regulation by LXRs is present in THP1 human cell line (data not shown) but occurs only at the protein level. This observation suggest that molecular mechanism underlying Eno1 regulation by LXRs is complex and probably organism specific. In the context of cellular cholesterol homeostasis regulation of Eno1 is of particular interest. There is ample evidence pin pointing changes in ENO1 abundance as a key determinant in the transformation of macrophages to “foam cells” in response to cholesterol loading [5], [6]. Shand and West [2] demonstrated that ENO1 inhibits activity of CEHs. Together with increased ENO1 expression this activity may contribute to enhanced-cholesteryl ester accumulation in macrophages loaded with lipoprotein-derived cholesterol. Whereas the roles of LXRs in cholesterol efflux and uptake are well established, their effect on cholesterol-ester storage is less-well studied. In this context, it is interesting to point out some oxysterols, which are endogenous LXR ligands, are reported to modulate cholesterol esterification by ACAT1 and 2 independent of LXRs activation [25], [26], [27], [28]. Nevertheless, mobilization of cholesterol from intracellular pools to the plasma membrane is an essential step in cholesterol efflux [29]. Indeed, NPC1 and NPC2 are required for efficient cholesterol efflux supported by cholesterol transporters such as ABCA1 and ABCG1 [30]. Furthermore, overexpression of CEH have been shown to enhances cholesterol elimination and reverse cholesterol transport in vivo[31]. Repression of Enolase expression by activated LXRs could therefore relieves their inhibition of CEH activity and enhances cholesteryl ester hydrolysis in macrophages. This in turn could provide a source of free cholesterol that is accessible to cholesterol efflux transporters (Fig. 5). In conclusion, Enolase repression by LXRs could represent a novel regulation node of cholesterol homeostasis network within the cell.