Glycogen Metabolism and Rheumatoid Arthritis: The Role of Glycogen Synthase 1 in Regulation of Synovial Inflammation via Blocking AMP-Activated Protein Kinase Activation.
Glycogen Metabolism and Rheumatoid Arthritis: The Role of Glycogen Synthase 1 in Regulation of Synovial Inflammation via Blocking AMP-Activated Protein Kinase Activation.
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糖原代谢和类风湿性关节炎：糖原合成酶 1 通过阻断 AMP 激活的蛋白激酶激活来调节滑膜炎症中的作用
DOI：
10.3389/fimmu.2018.01714
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发表时间：
2018
影响因子：
7.3
通讯作者：
Xu H
中科院分区：
文献类型：
--
作者：
Shi M;Wang J;Xiao Y;Wang C;Qiu Q;Lao M;Yu Y;Li Z;Zhang H;Ye Y;Liang L;Yang X;Chen G;Xu H
目的探讨糖原代谢在类风湿成纤维细胞样滑膜细胞（FLS）介导的滑膜炎症中的作用及其机制。方法从类风湿性关节炎（RA）患者的滑膜组织（STs）中分离FLSs。采用周期性酸性希夫染色法测定糖原含量。Western blot或免疫组化分析蛋白表达。实时荧光定量PCR检测细胞因子和基质金属蛋白酶（MMPs）的基因表达。EdU掺入法检测FLS增殖。博伊登室法测定迁移和侵袭。结果RA患者ST和fls中糖原水平和糖原合成酶1 （GYS1）表达显著升高。TNF-α或缺氧诱导RA FLSs中GYS1的表达和糖原合成。shRNA敲低GYS1可通过提高amp活化蛋白激酶（AMPK）活性，降低RA FLS中IL-1β、IL-6、CCL-2、MMP-1和MMP-9的表达及增殖和迁移。AMPK抑制剂或敲低AMPK可逆转GYS1敲低对RA FLSs炎症反应的抑制作用；然而，AMPK激动剂阻断RA FLS活性。我们进一步确定缺氧诱导因子-1α介导TNF-α-或缺氧诱导的GYS1表达和糖原水平。局部关节消耗GYS1或腹腔注射AMPK激动剂可改善胶原诱导关节炎大鼠的关节炎严重程度。结论gys1介导的糖原积累通过阻断AMPK激活参与fls介导的RA滑膜炎症。据我们所知，这是第一个将糖原代谢与慢性炎症联系起来的研究。抑制GYS1可能是治疗慢性炎症性关节炎（包括RA）的一种新的治疗策略。
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-induced arthritis. Conclusion Our data demonstrate that GYS1-mediated glycogen accumulation contributes to FLS-mediated synovial inflammation in RA by blocking AMPK activation. In our knowledge, this is a first study linking glycogen metabolism to chronic inflammation. Inhibition of GYS1 might be a novel therapeutic strategy for chronic inflammatory arthritis, including RA.
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影响因子：
3.7
作者：
Pescador N;Villar D;Cifuentes D;Garcia-Rocha M;Ortiz-Barahona A;Vazquez S;Ordoñez A;Cuevas Y;Saez-Morales D;Garcia-Bermejo ML;Landazuri MO;Guinovart J;del Peso L
通讯作者：
del Peso L
胰高血糖素样肽-1（GLP-1）类似物liraglutide通过钙和AMPK依赖机制抑制内皮细胞炎症。
影响因子：
3.7
作者：
Krasner NM;Ido Y;Ruderman NB;Cacicedo JM
通讯作者：
Cacicedo JM
DOI：
10.1074/jbc.m901790200
发表时间：
2009-06-19
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Mole DR;Blancher C;Copley RR;Pollard PJ;Gleadle JM;Ragoussis J;Ratcliffe PJ
通讯作者：
Ratcliffe PJ
影响因子：
2.7
作者：
Falantes, Jose F.;Trujillo, Pablo;Perez-Simon, Jose A.
通讯作者：
Perez-Simon, Jose A.
影响因子：
7.7
作者：
Pederson, BA;Schroeder, JM;Roach, PJ
通讯作者：
Roach, PJ