Glycogen Metabolism and Rheumatoid Arthritis: The Role of Glycogen Synthase 1 in Regulation of Synovial Inflammation via Blocking AMP-Activated Protein Kinase Activation

作者：Maohua Shi, Jingnan Wang, Youjun Xiao, Cuicui Wang, Qian Qiu, Minxi Lao, Yang-Tao Yu, Zhifeng Li, Hongwei Zhang, Yujin Ye, Liuqin Liang, Xiuyan Yang, Guoqiang Chen, Hanshi Xu · 发表于：Frontiers in Immunology · 年份：2018 · DOI：10.3389/fimmu.2018.01714 · 被引用次数：36 · 研究领域：Metabolism, Diabetes, and Cancer、Glycogen Storage Diseases and Myoclonus、Wnt/β-catenin signaling in development and cancer

Objective: To investigate the role of glycogen metabolism in regulating rheumatoid fibroblast-like synoviocyte (FLS)-mediated synovial inflammation and its underlying mechanism. Methods: FLSs were separated from synovial tissues (STs) obtained from rheumatoid arthritis (RA) patients. Glycogen content was determined by periodic acid Schiff staining. Protein expression was analyzed by Western blot or immunohistochemistry. Gene expression of cytokines and matrix metalloproteinases (MMPs) was evaluated by quantitative real-time PCR. FLS proliferation was detected by EdU incorporation. Migration and invasion were measured by Boyden chamber assay. Results: Glycogen levels and glycogen synthase 1 (GYS1) expression were significantly increased in the ST and FLSs of RA patients. TNF-α or hypoxia induced GYS1 expression and glycogen synthesis in RA FLSs. GYS1 knockdown by shRNA decreased the expression of IL-1β, IL-6, CCL-2, MMP-1, and MMP-9 and proliferation and migration by increasing AMP-activated protein kinase (AMPK) activity in RA FLS. AMPK inhibitor or knockdown AMPK could reverse the inhibitory effect of GYS1 knockdown on the inflammatory response in RA FLSs; however, an AMPK agonist blocked RA FLS activity. We further determined that hypoxia-inducible factor-1α mediates TNF-α- or hypoxia-induced GYS1 expression and glycogen levels. Local joint depletion of GYS1 or intraperitoneal administration with an AMPK agonist ameliorated the severity of arthritis in rats with collagen-in...