Linderane Suppresses Hepatic Gluconeogenesis by Inhibiting the cAMP/PKA/CREB Pathway Through Indirect Activation of PDE 3 via ERK/STAT3
文献类型：期刊论文
| 作者 | Xie, Wei1,2; Ye, Yangliang2 ; Feng, Ying2; Xu, Tifei2; Huang, Suling2; Shen, Jianhua2; Leng, Ying2
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| 刊名 | FRONTIERS IN PHARMACOLOGY
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| 出版日期 | 2018-05-15 |
| 卷号 | 9 |
| 关键词 | cAMP gluconeogenesis linderane phosphodiesterase type 2 diabetes |
| ISSN号 | 1663-9812 |
| DOI | 10.3389/fphar.2018.00476 |
| 文献子类 | Article |
| 英文摘要 | The role of phosphodiesterase 3 (PDE3), a cyclic AMP (cAMP)-degrading enzyme, in modulating gluconeogenesis remains unknown Here, linderane, a natural compound, was found to inhibit gluconeogenesis by activating hepatic PDE3 in rat primary hepatocytes. The underlying molecular mechanism and its effects on wholebody glucose and lipid metabolism were investigated. The effect of linderane on gluconeogenesis, cAMP content, phosphorylation of cAMP-response element-binding protein (CREB) and PDE activity were examined in cultured primary hepatocytes and C57BL/6J mice. The precise mechanism by which linderane activates PDE3 and inhibits the cAMP pathway was explored using pharmacological inhibitors. The amelioration of metabolic disorders was observed in ob/ob mice. Linderane inhibited gluconeogenesis, reduced phosphoenolpyruvate carboxykinase (Pck1) and glucose-6-phosphatase (G6pc) gene expression, and decreased intracellular cAMP concentration and CREB phosphorylation in rat primary hepatocytes under both basal and forskolinstimulated conditions. In rat primary hepatocytes, it also increased total PDE and PDE3 activity but not PDE4 activity. The suppressive effect of linderane on the cAMP pathway and gluconeogenesis was abolished by the non-specific PDE inhibitor 3-isobutyl-1 -methylxanthine (IBMX) and the specific PDE3 inhibitor cilostazol Linderane indirectly activated PDE3 through extracellular regulated protein kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) activation Linderane improved glucose and lipid metabolism after chronic oral administration in ob/ob mice. Our findings revealed linderane as an indirect PDE3 activator that suppresses gluconeogenesis through cAMP pathway inhibition and has beneficial effects on metabolic syndromes in ob/ob mice. This investigation highlighted the potential for PDE3 activation in the treatment of type 2 diabetes. |
| WOS关键词 | ISOLATED RAT HEPATOCYTES ; CYCLIC-AMP ; GLUCOSE-HOMEOSTASIS ; BINDING-PROTEIN ; INSULIN ; GLUCAGON ; PHOSPHORYLATION ; METABOLISM ; CREB ; PATHOGENESIS |
| 资助项目 | State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM1601ZZ-02] ; Independent Research Project of the Institute of Pharmaceutical Innovation (Chinese Academy of Sciences)[CASIMM0120162022] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000432302600002 |
| 出版者 | FRONTIERS MEDIA SA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279759]  |
| 专题 | 药理学第一研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药物发现与设计中心 |
| 通讯作者 | Huang, Suling; Shen, Jianhua; Leng, Ying |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Xie, Wei,Ye, Yangliang,Feng, Ying,et al. Linderane Suppresses Hepatic Gluconeogenesis by Inhibiting the cAMP/PKA/CREB Pathway Through Indirect Activation of PDE 3 via ERK/STAT3[J]. FRONTIERS IN PHARMACOLOGY,2018,9. |
| APA | Xie, Wei.,Ye, Yangliang.,Feng, Ying.,Xu, Tifei.,Huang, Suling.,...&Leng, Ying.(2018).Linderane Suppresses Hepatic Gluconeogenesis by Inhibiting the cAMP/PKA/CREB Pathway Through Indirect Activation of PDE 3 via ERK/STAT3.FRONTIERS IN PHARMACOLOGY,9. |
| MLA | Xie, Wei,et al."Linderane Suppresses Hepatic Gluconeogenesis by Inhibiting the cAMP/PKA/CREB Pathway Through Indirect Activation of PDE 3 via ERK/STAT3".FRONTIERS IN PHARMACOLOGY 9(2018). |
入库方式： OAI收割
来源：上海药物研究所
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