Phosphorylation of Liver X Receptor α Selectively Regulates Target Gene Expression in Macrophages

Abstract

Dysregulation of liver X receptor ␣ (LXR␣) activity has been linked to cardiovascular and metabolic diseases. Here, we show that LXR␣ target gene selectivity is achieved by modulation of LXR␣ phosphorylation. Under basal conditions, LXR␣ is phosphorylated at S198; phosphorylation is enhanced by LXR ligands and reduced both by casein kinase 2 (CK2) inhibitors and by activation of its heterodimeric partner RXR with 9-cis-retinoic acid (9cRA). Expression of some (AIM and LPL), but not other (ABCA1 or SREBPc1) established LXR target genes is increased in RAW 264.7 cells expressing the LXR␣ S198A phosphorylation-deficient mutant compared to those with WT receptors. Surprisingly, a gene normally not expressed in macrophages, the chemokine CCL24, is activated specifically in cells expressing LXR␣ S198A. Furthermore, inhibition of S198 phosphorylation by 9cRA or by a CK2 inhibitor similarly promotes CCL24 expression, thereby phenocopying the S198A mutation. Thus, our findings reveal a previously unrecognized role for phosphorylation in restricting the repertoire of LXR␣-responsive genes.

Nuclear Receptor Liver X Receptor Is O-GlcNAc-modified in Response to Glucose

“…However, we cannot exclude that LXR O-GlcNAcylation may be positively or negatively regulated by LXR and/or RXR ligand because a recent study by Torra et al (17) reported that Ser 198 phosphorylation of LXR␣ in RAW macrophages was induced by both synthetic and natural oxysterol LXR ligands and reduced by the RXR ligand 9-cis-retinoc acid. Additionally, in our study we see a robust induction of hepatic SREBP-1c mRNA expression by glucose in vivo not observed in LXR ␣/␤ double knock-out mice (Fig.…”

“…Human LXR␣ has been shown to be phosphorylated on serine 198 (15,17), affecting transcription in a gene-specific manner in macrophages (17). Because other serine or threonine residues may be phosphorylated upon protein kinase A signaling, it is currently not known whether Ser 198 is the site of protein kinase A phosphorylation on human LXR in the liver.…”

“…LXRs are shown to be post-translationally modified by phosphorylation (15)(16)(17), acetylation (18), and sumoylation (19), affecting their target gene specificity, stability, and transactivating and transrepressional activity, respectively. Recently, Mitro et al (20) showed that physiological concentrations of glucose were able to activate LXR and induce expression of genes involved in both lipid and cholesterol homeostasis in liver.…”

Biological Roles of Liver X Receptors in Immune Cells

“…Phosphorylation of LXRa on this site seems to exert repressive effects on AIM expression, as overexpression of LXRa with a mutation at serine 198 resulted in increased induction of AIM in response to the LXR agonist TO901317. These effects were specific toward selective LXR targets, also including lipoprotein lipase, but not ABCA-1 and SREBP-1c (Torra et al 2008). Whether this selective modulation of target genes also occurs in vivo deserves to be uncovered in the future.…”

The Role of Liver X Receptor in Hepatic de novo Lipogenesis and Cross-Talk with Insulin and Glucose Signaling

“…Furthermore, GlcNAcylation and phosphorylation of LXR might be affected by ligand binding, which has been shown for SUMOylation and acetylation of LXR (Venteclef et al, 2010;Lee et al, 2009). A study by Torra et al (Torra et al, 2008) reported that Ser 198 phosphorylation of LXR in RAW macrophages was induced by both synthetic and natural oxysterol LXR ligands and reduced by the RXR ligand 9-cis-retinoc acid. As such, we cannot exclude the possibility that LXR O-GlcNAcylation may be positively or negatively regulated by LXR and/or RXR ligands.…”