The Liver X Receptor Is Upregulated in Monocyte-Derived Macrophages and Modulates Inflammatory Cytokines Based on LXRα Polymorphism

Abstract

Liver X receptors (LXRs) have emerged as important regulators of inflammatory gene expression. Previously, we had reported that an LXRα gene promoter polymorphism (-1830 T > C) is associated with systemic lupus erythematosus (SLE). Therefore, we assessed cytokine expression in relation to LXRα polymorphism in monocyte-derived macrophages from patients with SLE. Macrophages were obtained after 72 hours of culture of human monocytes supplemented with phorbol 12-myristate 13-acetate. Cells were transfected with LXRα promoter constructs. Additionally, peripheral blood mononuclear cell- (PBMC-) derived macrophages from the patients were evaluated for proinflammatory cytokines in relation to the genotypes of LXRα -1830 T > C. The expression of LXRα was increased in macrophages; levels of proinflammatory cytokines were decreased with LXRα expression. Production of proinflammatory cytokines varied depending on LXRα -1830 T > C genotype. In particular, expression of LXRα was decreased and that of proinflammatory cytokines was increased for LXRα -1830 TC genotype compared to that for TT genotype. The data were consistent in PBMC-derived macrophages from patients with SLE. Increased proinflammatory cytokines is related to TLR7 and TLR9 expression. These data suggest that the expression levels of LXRα, according to LXRα -1830 T > C genotype, may contribute to the inflammatory response by induction of inflammatory cytokines in SLE.

Activation of liver X receptors suppresses the abundance and osteoclastogenic potential of osteoclast precursors and periodontal bone loss

“…It has also been reported that long‐term LXR activation potentiates pro‐inflammatory cytokine secretion in LPS‐stimulated human macrophages (Fontaine et al., 2007). Others have reported that LXR activation does not alter the secretion of pro‐inflammatory cytokines in macrophages following inflammatory stimulation (Kim et al., 2019). In the context of bone remodeling, LXRs have been found to play a dual role on osteoblasts and osteoclasts.…”

Metabolic alterations in vitamin D deficient systemic lupus erythematosus patients

“…Fatty acids could modulate the process of macrophage differentiation 28 . Targeting receptors associated lipid metabolism, such as peroxisome proliferator-activated receptor γ (PPARγ), 12/15-Lipoxygenase (12/15-LO), sphingosine-1phosphate (S1P) and liver X receptors (LXRs), was able to affect differentiation of monocytes and production of proin ammatory cytokines, which were related to TLR7 and TLR9 expression [29][30][31][32] . Furthermore, we observed strong associations between the differential metabolites, particularly the lipids, suggesting that these metabolites may participate in the same metabolic pathway, or biological process.…”

PAL inhibits foam cell formation by regulating the PPAR-γ signaling pathway in oxidized low-density lipoprotein-induced THP-1 macrophages

“…Through these effects, it mediates the decomposition transport and effluence of cholesterol, and plays a key role in regulating the occurrence and progression of foam cell formation [31][32][33][34][35][36][37]. In addition, PPAR-γ inhibits monocyte/macrophage activation, reduces inflammatory cell infiltration, and decreases the release of inflammatory factors [38][39][40]. Thus, it is closely related to the regulation of macrophage inflammation.…”