The importance of the Liver X receptors (LXRs) as a critical modulators of metabolic homeostasis and immunity in health and disease has been mainly gleaned from studies evaluating the consequences of their pharmacological or genetic manipulation. We previously showed LXRα is phosphorylated upon cholesterol loading. It is however unknown whether post-translational modifications of the receptor modulate diet-induced responses and affect metabolic diseases with an important inflammatory component. To explore the impact of LXRα phosphorylation in disease progression we have generated two models: i) a whole-body phosphorylation-deficient mutant of LXRα at S196A (S196A) in which we explored the progression of non-alcoholic fatty liver disease and ii) a phospho-deficient LXRa mutant in myeloid cells (M-LXRαS196A) on the atherosclerotic LDLR null background (M-LXRαS196ALdlr-KO) in which we examined the development of atherosclerosis.
S196A mice challenged with a High Fat-High Cholesterol diet exhibit reduced hepatic inflammation and fibrosis associated with a marked protection against cholesterol accumulation. Impaired LXRα phosphorylation in this model uncovers novel diet-specific/phosphorylation-sensitive genes. Furthermore, M-LXRαS196ALdlr-KO fed a High-Fat diet display a significant increase in atherosclerosis burden in the absence of altered systemic lipid levels. Reduced LXRα phosphorylation during atherogenesis reprograms the macrophage transcriptome and significantly promotes cell proliferation pathways, which is a feature of developing atherosclerotic lesions. Interestingly, the global gene expression changes observed in response to impaired LXRα phosphorylation are fundamentally different from those revealed by ligand activation highlighting the importance of this post-translational modification in modulating the activity of the receptor in the context of metabolic/inflammatory diseases.
Overall, we show the relevance of manipulating Ser196-LXRα phosphorylation to promote unique transcriptomes, thereby specifically modulating pathways important for the development of metabolic diseases such as non-alcoholic fatty liver disease and atherosclerosis.
27 Feb - 02 Mar 2018
Nuclear Receptors Conference