Coronarin A modulated hepatic glycogen synthesis and gluconeogenesis via inhibiting mTORC1/S6K1 signaling and ameliorated glucose homeostasis of diabetic mice
文献类型：期刊论文
| 作者 | Huang, Su-Ling3 ; Xie, Wei2,3; Ye, Yang-Liang3; Liu, Jia1; Qu, Hui3; Shen, Yu3; Xu, Ti-Fei3; Zhao, Zhuo-Hui2,3; Shi, Yu2,3; Shen, Jian-Hua3
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2022-09-09 |
| 页码 | 14 |
| ISSN号 | 1671-4083 |
| 关键词 | type 2 diabetes mellitus coronarin A glycogen synthesis gluconeogenesis mTORC1 IRS1 |
| DOI | 10.1038/s41401-022-00985-5 |
| 通讯作者 | Shen, Jian-Hua(jhshen@simm.ac.cn) ; Leng, Ying(yleng@simm.ac.cn) |
| 英文摘要 | Promotion of hepatic glycogen synthesis and inhibition of hepatic glucose production are effective strategies for controlling hyperglycemia in type 2 diabetes mellitus (T2DM), but agents with both properties were limited. Herein we report coronarin A, a natural compound isolated from rhizomes of Hedychium gardnerianum, which simultaneously stimulates glycogen synthesis and suppresses gluconeogenesis in rat primary hepatocytes. We showed that coronarin A (3, 10 mu M) dose-dependently stimulated glycogen synthesis accompanied by increased Akt and GSK3 beta phosphorylation in rat primary hepatocytes. Pretreatment with Akt inhibitor MK-2206 (2 mu M) or PI3K inhibitor LY294002 (10 mu M) blocked coronarin A-induced glycogen synthesis. Meanwhile, coronarin A (10 mu M) significantly suppressed gluconeogenesis accompanied by increased phosphorylation of MEK, ERK1/2, beta-catenin and increased the gene expression of TCF7L2 in rat primary hepatocytes. Pretreatment with beta-catenin inhibitor IWR-1-endo (10 mu M) or ERK inhibitor SCH772984 (1 mu M) abolished the coronarin A-suppressed gluconeogenesis. More importantly, we revealed that coronarin A activated PI3K/Akt/GSK3 beta and ERK/Wnt/beta-catenin signaling via regulation of a key upstream molecule IRS1. Coronarin A (10, 30 mu M) decreased the phosphorylation of mTOR and S6K1, the downstream target of mTORC1, which further inhibited the serine phosphorylation of IRS1, and subsequently increased the tyrosine phosphorylation of IRS1. In type 2 diabetic ob/ob mice, chronic administration of coronarin A significantly reduced the non-fasting and fasting blood glucose levels and improved glucose tolerance, accompanied by the inhibited hepatic mTOR/S6K1 signaling and activated IRS1 along with enhanced PI3K/Akt/GSK3 beta and ERK/Wnt/beta-catenin pathways. These results demonstrate the anti-hyperglycemic effect of coronarin A with a novel mechanism by inhibiting mTORC1/S6K1 to increase IRS1 activity, and highlighted coronarin A as a valuable lead compound for the treatment of T2DM. |
| WOS关键词 | INSULIN-RESISTANCE ; LIVER ; METABOLISM ; PATHWAY ; HYPERGLYCEMIA ; PATHOGENESIS ; OBESITY ; KINASE ; MTORC2 ; MODEL |
| 资助项目 | Foundation of Shanghai Science and Technology Committee[21DZ2291100] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | NATURE PUBL GROUP |
| WOS记录号 | WOS:000852117900001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/302417]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Shen, Jian-Hua; Leng, Ying |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Huang, Su-Ling,Xie, Wei,Ye, Yang-Liang,et al. Coronarin A modulated hepatic glycogen synthesis and gluconeogenesis via inhibiting mTORC1/S6K1 signaling and ameliorated glucose homeostasis of diabetic mice[J]. ACTA PHARMACOLOGICA SINICA,2022:14. |
| APA | Huang, Su-Ling.,Xie, Wei.,Ye, Yang-Liang.,Liu, Jia.,Qu, Hui.,...&Leng, Ying.(2022).Coronarin A modulated hepatic glycogen synthesis and gluconeogenesis via inhibiting mTORC1/S6K1 signaling and ameliorated glucose homeostasis of diabetic mice.ACTA PHARMACOLOGICA SINICA,14. |
| MLA | Huang, Su-Ling,et al."Coronarin A modulated hepatic glycogen synthesis and gluconeogenesis via inhibiting mTORC1/S6K1 signaling and ameliorated glucose homeostasis of diabetic mice".ACTA PHARMACOLOGICA SINICA (2022):14. |
入库方式： OAI收割
来源：上海药物研究所
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