Inhibiting LXRα Phosphorylation in Hematopoietic Cells Reduces Inflammation and Attenuates Atherosclerosis and Obesity

Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXR, a nuclear receptor, plays a central role in the transcription of inflammatory and lipid metabolic genes. LXR is modulated by phosphorylation at serine 196 (LXR pS196), however, the functional consequences of LXR pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXR phosphorylation, bone marrow from LXRWT and S196A mice was transplanted into Ldlr-/- mice, which were fed a high fat, high cholesterol diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68+ cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXR pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXR to an anti-inflammatory phenotype.