Phosphorylation of liver x receptor α selectively regulates target gene expression in macrophages

Dysregulation of liver X receptor alpha (LXR alpha) activity has been linked to cardiovascular and metabolic diseases. Here, we show that LXR alpha target gene selectivity is achieved by modulation of LXR alpha phosphoryllation. Under basal conditions, LXR alpha is phosphorylated at S198A phosphoryllation 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 alpha 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 alpha 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 phosphoryllation in restricting the repertoire of LXR alpha-responsive genes.