ABSTRACT
Overnutrition causes obesity, a global health problem without any effective therapy. Obesity is characterized by low-grade inflammation, which predisposes individuals to metabolic syndrome via unknown mechanisms. Here, we demonstrate that abolishing the interleukin-17A (IL-17A) axis in mice by inhibition of RORγt-mediated IL-17A production by digoxin, or by ubiquitous deletion of IL-17 receptor A (Il17ra), suppresses diet-induced obesity (DIO) and metabolic disorders, and promotes adipose-tissue browning, thermogenesis and energy expenditure. Genetic ablation of Il17ra specifically in adipocytes is sufficient to completely prevent DIO and metabolic dysfunction in mice. IL-17A produced in response to DIO induces PPARγ phosphorylation at Ser273 in adipocytes in a CDK5-dependent manner, thereby modifying expression of diabetogenic and obesity genes, which correlates with IL-17A signalling in white adipose tissues of individuals with morbid obesity. These findings reveal an unanticipated role for IL-17A in adipocyte biology, in which its direct action pathogenically reprograms adipocytes, promoting DIO and metabolic syndrome. Targeting the IL-17A axis could be an efficient antiobesity strategy.
Subject(s)
Adipocytes/drug effects , Interleukin-17/antagonists & inhibitors , Metabolic Diseases/prevention & control , Obesity/prevention & control , Adipose Tissue, Brown/physiology , Animals , Cyclin-Dependent Kinase 5/metabolism , Diet , Diet, High-Fat , Digoxin/pharmacology , Energy Metabolism/physiology , Feces/chemistry , Gene Deletion , Mice , Mice, Inbred C57BL , Mice, Knockout , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Overnutrition , PPAR gamma/metabolism , Phosphorylation , Thermogenesis/physiologyABSTRACT
STAG2, a cohesin family gene, is among the most recurrently mutated genes in cancer. STAG2 loss of function (LOF) is associated with aggressive behavior in Ewing sarcoma, a childhood cancer driven by aberrant transcription induced by the EWSR1-FLI1 fusion oncogene. Here, using isogenic Ewing cells, we show that, while STAG2 LOF profoundly changes the transcriptome, it does not significantly impact EWSR1-FLI1, CTCF/cohesin, or acetylated H3K27 DNA binding patterns. In contrast, it strongly alters the anchored dynamic loop extrusion process at boundary CTCF sites and dramatically decreases promoter-enhancer interactions, particularly affecting the expression of genes regulated by EWSR1-FLI1 at GGAA microsatellite neo-enhancers. Down-modulation of cis-mediated EWSR1-FLI1 activity, observed in STAG2-LOF conditions, is associated with enhanced migration and invasion properties of Ewing cells previously observed in EWSR1-FLI1low cells. Our study illuminates a process whereby STAG2-LOF fine-tunes the activity of an oncogenic transcription factor through altered CTCF-anchored loop extrusion and cis-mediated enhancer mechanisms.
Subject(s)
Bone Neoplasms/genetics , CCCTC-Binding Factor/metabolism , Cell Cycle Proteins/genetics , Oncogene Proteins, Fusion/genetics , Sarcoma, Ewing/genetics , Bone Neoplasms/mortality , Bone Neoplasms/pathology , CCCTC-Binding Factor/chemistry , CCCTC-Binding Factor/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Movement/genetics , Chromatin Immunoprecipitation , Chromosomal Proteins, Non-Histone/metabolism , Enhancer Elements, Genetic , Gene Expression Regulation, Neoplastic , Histones/metabolism , Humans , Loss of Function Mutation , Lysine/metabolism , Oncogene Proteins, Fusion/metabolism , Promoter Regions, Genetic , Sarcoma, Ewing/mortality , Sarcoma, Ewing/pathology , CohesinsABSTRACT
OBJECTIVES: SLE patients have an enhanced risk of atherosclerosis and cardiovascular disease. However, the increased prevalence of cardiovascular disease is not fully explained by traditional Framingham cardiovascular risk factors. Specific features of low-density lipoprotein (LDL) particles, other than plasma concentration, may induce accelerated atherosclerosis at early stages in these patients. Thus, we aimed to explore the impact of LDL from both active and inactive SLE patients on human aortic endothelial cells. METHODS: Human aortic endothelial cells were stimulated with the same concentration of LDL particles isolated from pooled serum that was collected from 13 SLE patients during both active and inactive states. Gene expression and cell migration assays were performed. RESULTS: Circulating LDL particles obtained from healthy volunteers and SLE patients in both remission and flare states were comparable in terms of number, cholesterol and triglyceride content, and net electric charge. Stimulation of cells with LDL from active SLE patients induced the expression of vascular cell adhesion molecule 1 (â¼2.0-fold, P < 0.05), monocyte chemoattractant protein 1 (â¼2.0-fold, P < 0.05) and matrix metallopeptidase 2 (â¼1.6-fold, P < 0.01) compared with cells stimulated with LDL from inactive SLE patients. Additionally, LDL extracted from active patients increased cell migration in a wound-healing assay (1.4-fold, P < 0.05). CONCLUSION: Our data show that, at the same LDL concentration, LDL from active SLE patients had increased proatherogenic effects on endothelial cells compared with LDL from the same patients when in an inactive or remission state.
