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Activation of SIK1 by phanginin A inhibits hepatic gluconeogenesis by increasing PDE4 activity and suppressing the cAMP signaling pathway

文献类型：期刊论文

作者Liu, Siwen1,2; Huang, Suling1; Wu, Xingde; Feng, Ying1; Shen, Yu1; Zhao, Qin-shi3; Leng, Ying1,2
刊名MOLECULAR METABOLISM
出版日期2020-11-01
卷号41页码:15
ISSN号2212-8778
关键词Salt-inducible kinase 1 Phanginin A Phosphodiesterase 4 Gluconeogenesis cAMP
DOI10.1016/j.molmet.2020.101045
通讯作者Zhao, Qin-shi(qinshizhao@mail.kib.ac.cn) ; Leng, Ying(yleng@simm.ac.cn)
英文摘要Objective: Salt-induced kinase 1 (SIK1) acts as a key modulator in many physiological processes. However, the effects of SIK1 on gluconeogenesis and the underlying mechanisms have not been fully elucidated. In this study, we found that a natural compound phanginin A could activate SIK1 and further inhibit gluconeogenesis. The mechanisms by which phanginin A activates SIK1 and inhibits gluconeogenesis were explored in primary mouse hepatocytes, and the effects of phanginin A on glucose homeostasis were investigated in ob/ob mice. Methods: The effects of phanginin A on gluconeogenesis and SIK1 phosphorylation were examined in primary mouse hepatocytes. Pan-SIK inhibitor and siRNA-mediated knockdown were used to elucidate the involvement of SIK1 activation in phanginin A-reduced gluconeogenesis. LKB1 knockdown was used to explore how phanginin A activated SIK1. SIK1 overexpression was used to evaluate its effect on gluconeogenesis, PDE4 activity, and the cAMP pathway. The acute and chronic effects of phanginin A on metabolic abnormalities were observed in ob/ob mice. Results: Phanginin A significantly increased SIK1 phosphorylation through LKB1 and further suppressed gluconeogenesis by increasing PDE4 activity and inhibiting the cAMP/PKA/CREB pathway in primary mouse hepatocytes, and this effect was blocked by pan-SIK inhibitor HG-9-91-01 or siRNA-mediated knockdown of SIK1. Overexpression of SIK1 in hepatocytes increased PDE4 activity, reduced cAMP accumulation, and thereby inhibited gluconeogenesis. Acute treatment with phanginin A reduced gluconeogenesis in vivo, accompanied by increased SIK1 phosphorylation and PDE4 activity in the liver. Long-term treatment of phanginin A profoundly reduced blood glucose levels and improved glucose tolerance and dyslipidemia in ob/ob mice. Conclusion: We discovered an unrecognized effect of phanginin A in suppressing hepatic gluconeogenesis and revealed a novel mechanism that activation of SIK1 by phanginin A could inhibit gluconeogenesis by increasing PDE4 activity and suppressing the cAMP/PKA/CREB pathway in the liver. We also highlighted the potential value of phanginin A as a lead compound for treating type 2 diabetes. (C) 2020 The Author(s). Published by Elsevier GmbH.
WOS关键词INDUCIBLE KINASE 1 ; MODULATES GLUCONEOGENESIS ; GLUCOSE-METABOLISM ; CREB ; GLUCAGON ; DITERPENOIDS ; SEEDS
资助项目National Science and Technology Major Project-Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-006-012] ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM1903KF-08] ; Science and Technology Commission of Shanghai Municipality[19ZR1467600]
WOS研究方向Endocrinology & Metabolism
语种英语
出版者ELSEVIER
WOS记录号WOS:000580985700005
源URL[http://119.78.100.183/handle/2S10ELR8/291487]  
专题新药研究国家重点实验室
通讯作者Zhao, Qin-shi; Leng, Ying
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650201, Yunnan, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Siwen,Huang, Suling,Wu, Xingde,et al. Activation of SIK1 by phanginin A inhibits hepatic gluconeogenesis by increasing PDE4 activity and suppressing the cAMP signaling pathway[J]. MOLECULAR METABOLISM,2020,41:15.
APA Liu, Siwen.,Huang, Suling.,Wu, Xingde.,Feng, Ying.,Shen, Yu.,...&Leng, Ying.(2020).Activation of SIK1 by phanginin A inhibits hepatic gluconeogenesis by increasing PDE4 activity and suppressing the cAMP signaling pathway.MOLECULAR METABOLISM,41,15.
MLA Liu, Siwen,et al."Activation of SIK1 by phanginin A inhibits hepatic gluconeogenesis by increasing PDE4 activity and suppressing the cAMP signaling pathway".MOLECULAR METABOLISM 41(2020):15.

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来源：上海药物研究所

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