Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels
文献类型：期刊论文
| 作者 | Liu, Wen2; Yin, Ye3; Wang, Meijing2; Fan, Ting2; Zhu, Yuyu2; Shen, Lihong2; Peng, Shuang2; Gao, Jian2; Deng, Guoliang2; Meng, Xiangbao4 |
| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
 |
| 出版日期 | 2020-07-31 |
| 卷号 | 295期号:31页码:10842-10856 |
| 关键词 | Src homology 2 domain containing tyrosine phosphatase-2 (SHP2) hepatic steatosis insulin resistance caspase-1 interleukin 18 (IL-18) fatty liver metabolic disorder inflammation cytokine signaling caspase 1 (CASP1) tyrosine-protein phosphatase (tyrosine phosphatase) macrophage |
| ISSN号 | 0021-9258 |
| DOI | 10.1074/jbc.RA119.011840 |
| 通讯作者 | Guo, Wenjie(guowj@nju.edu.cn) ; Xu, Qiang(molpharm@163.com) ; Sun, Yang(yangsun@nju.edu.cn) |
| 英文摘要 | Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, bothin vivoandin vitro. Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes. |
| WOS关键词 | TYROSINE-PHOSPHATASE ; NLRP3 INFLAMMASOME ; ENERGY-BALANCE ; BODY-WEIGHT ; INTERLEUKIN-18 ; OBESITY ; INHIBITION ; IL-1-BETA ; CYTOKINES ; DELETION |
| 资助项目 | National Natural Science Foundation of China[91853109] ; National Natural Science Foundation of China[81872877] ; National Natural Science Foundation of China[81730100] ; National Natural Science Foundation of China[81922067] ; National Natural Science Foundation of China[81673436] ; National Natural Science Foundation of China[81970709] ; Open Fund of State Key Laboratory of Drug Research[SIMM1903KF-10] ; Fundamental Research Funds for the Central Universities[14380114] ; Fundamental Research Funds for the Central Universities[14380128] ; Mountain-Climbing Talents Project of Nanjing University |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000560405600026 |
| 出版者 | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/292373]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Guo, Wenjie; Xu, Qiang; Sun, Yang |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 2.Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Dept Biotechnol & Pharmaceut Sci, Sch Life Sci, Nanjing, Peoples R China 3.Nanjing Med Univ, Dept Biochem & Mol Biol, Key Lab Human Funct Genom Jiangsu Prov, Nanjing, Peoples R China 4.Peking Univ, Sch Pharmaceut Sci, Dept Biol Chem, State Key Lab Nat & Biomimet Drugs, Beijing, Peoples R China 5.Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA 6.Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA 7.Nanjing Univ, Chem & Biomed Innovat Ctr ChemBIC, Nanjing, Peoples R China |
| 推荐引用方式 GB/T 7714 | Liu, Wen,Yin, Ye,Wang, Meijing,et al. Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2020,295(31):10842-10856. |
| APA | Liu, Wen.,Yin, Ye.,Wang, Meijing.,Fan, Ting.,Zhu, Yuyu.,...&Sun, Yang.(2020).Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels.JOURNAL OF BIOLOGICAL CHEMISTRY,295(31),10842-10856. |
| MLA | Liu, Wen,et al."Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels".JOURNAL OF BIOLOGICAL CHEMISTRY 295.31(2020):10842-10856. |
入库方式： OAI收割
来源：上海药物研究所
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