Biology subjects

Shrestha, E.

Publications and source records attributed to Shrestha, E..

2 recordsLinked to original sources

bioRxiv2018

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

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.

genetics↗

bioRxiv2017

Changes In LXRα Phosphorylation Promote A Novel Diet-Induced Transcriptome That Alters The Transition From Fatty Liver To Steatohepatitis

Understanding the transition from fatty liver or steatosis to more advanced inflammatory and fibrotic stages of non-alcoholic fatty liver disease (steatohepatitis), is key to define strategies that alter or even reverse the progression of this pathology. The Liver X Receptor alpha (LXR) controls hepatic lipid homeostasis and inflammation. Here we show that mice carrying a mutation that abolishes phosphorylation at Ser196 (S196A) in LXR exhibit reduced hepatic inflammation and fibrosis when challenged with a high fat-high cholesterol diet, despite displaying enhanced hepatic lipid accumulation. This protective effect is associated with reduced cholesterol accumulation, a key promoter of lipid-mediated hepatic damage. Reduced steatohepatitis in S196A mice involves the reprogramming of the liver transcriptome by promoting diet-induced changes in the expression of genes involved in endoplasmic reticulum stress, extracellular matrix remodelling, inflammation and lipid metabolism. Unexpectedly, changes in LXR phosphorylation uncover novel diet-specific target genes, whose regulation does not simply mirror ligand-induced LXR activation. These unique LXR phosphorylation-sensitive, diet-responsive target genes are revealed by promoting LXR occupancy and cofactor recruitment in the context of a cholesterol-rich diet. Therefore, LXR phosphorylation at Ser196 critically acts as a novel nutritional sensor that promotes a unique diet-induced transcriptome thereby modulating metabolic, inflammatory and fibrotic responses important in the transition to steatohepatitis.

pathology↗