Phosphorylation of LXRα impacts atherosclerosis regression by modulating monocyte/macrophage trafficking

Abstract

LXR activation in macrophages enhances regression of atherosclerotic plaques in mice by regulating genes crucial for cholesterol efflux, cell motility and inflammation. Diabetes, however, impairs plaque regression in mice. LXR is phosphorylated at serine 198 (pS198), which affects the expression of genes controlling inflammation, lipid metabolism and cell movement. We hypothesize that LXR function is affected by hyperglycemia through changes in LXR pS198. Indeed, macrophages cultured in diabetes relevant high glucose versus normal glucose display alterations in LXR-dependent gene expression and increased LXR pS198. We therefore examined the consequence of disrupting LXR phosphorylation (S196A in mouse LXR) during regression of atherosclerosis in normal and diabetic mice. We find that phosphorylation deficient LXR S196A reduces macrophage retention in plaques in diabetes, which is predicted to be anti-atherogenic and enhance plaque regression. However, this favorable effect on regression is masked by increased monocyte infiltration in the plaque attributed to leukocytosis in LXR S196A mice. RNA-seq of plaque macrophages from diabetic S196A mice shows increased expression of chemotaxis and decreased expression of cell adhesion genes, consistent with reduced macrophage retention by LXR S196A. Thus, the non-phosphorylated form of LXR precludes macrophage retention in the plaque. Our study provides the first evidence for a physiological role of LXR phosphorylation in modulating atherosclerosis regression. Compounds that prevent LXR phosphorylation or ligands that induce the conformation of non-phosphorylated LXR may selectively enhance macrophage emigration from atherosclerotic plaques.