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Sustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14

文献类型：期刊论文

作者Liu, Bin6,7; Zhang, Zhijian5; Hu, Yanyun5; Lu, Yan4,7; Li, Duanzhuo6; Liu, Jie6; Liao, Shengjie6; Hu, Min6; Wang, Yuxing6; Zhang, Die6
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2019-10-22
卷号116期号:43页码:21732-21738
关键词type 2 diabetes gluconeogenesis hepatic glucose production ER stress USP14
ISSN号0027-8424
DOI10.1073/pnas.1907288116
通讯作者Xiong, Xuelian(xiong.xuelian@zs-hospital.sh.cn) ; Li, Xiaoying(li.xiaoying@zs-hospital.sh.cn)
英文摘要Endoplasmic reticulum ( ER) stress plays an important role in metabolic diseases like obesity and type 2 diabetes mellitus (T2DM), although the underlying mechanisms and regulatory pathways remain to be elucidated. Here, we induced chronic low-grade ER stress in lean mice to levels similar to those in high-fat diet (HFD)-fed obese mice and found that it promoted hyperglycemia due to enhanced hepatic gluconeogenesis. Mechanistically, sustained ER stress up-regulated the deubiquitinating enzyme ubiquitin-specific peptidase 14 (USP14), which increased the stability and levels of 3',5'-cyclic monophosphate-responsive element binding (CREB) protein (CBP) to enhance glucagon action and hepatic gluconeogenesis. Exogenous overexpression of USP14 in the liver significantly increased hepatic glucose output. Consistent with this, liver-specific knockdown of USP14 abrogated the effects of ER stress on glucose metabolism, and also improved hyperglycemia and glucose intolerance in obese mice. In conclusion, our findings show a mechanism underlying ER stress-induced disruption of glucose homeostasis, and present USP14 as a potential therapeutic target against T2DM.
WOS关键词ENDOPLASMIC-RETICULUM STRESS ; UNFOLDED PROTEIN RESPONSE ; HEPATIC GLUCOSE-METABOLISM ; INSULIN-RESISTANCE ; CREB ; PHOSPHORYLATION ; GLUCONEOGENESIS ; HOMEOSTASIS ; OBESITY ; ACTIVATION
资助项目National Key Research and Development Program of China[2016YFC1304801] ; National Natural Science Foundation of China[31530033] ; National Natural Science Foundation of China[81773018] ; National Natural Science Foundation of China[81500617] ; National Natural Science Foundation of China[81600372] ; Science and Technology Commission of ShanghaiMunicipality[16JC1404100] ; Shanghai Municipal Health Bureau[20184Y0284]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000491366700058
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/282679]  
专题新药研究国家重点实验室
通讯作者Xiong, Xuelian; Li, Xiaoying
作者单位1.Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Shanghai Clin Ctr Diabet, Shanghai Diabet Inst,Shanghai Key Lab Diabet Mel, Shanghai 200233, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Fudan Univ, Sch Med, Zhongshan Hosp, Inst Clin Sci, Shanghai 200032, Peoples R China
4.Fudan Univ, Minist Educ, Key Lab Metab & Mol Med, Shanghai 20032, Peoples R China
5.Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Endocrinol & Metab, Shanghai 201620, Peoples R China
6.Hubei Polytech Univ, Sch Med, Hubei Key Lab Kidney Dis Pathogenesis & Intervent, Huangshi 435003, Hubei, Peoples R China
7.Fudan Univ, Zhongshan Hosp, Dept Endocrinol & Metab, Shanghai 20032, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Bin,Zhang, Zhijian,Hu, Yanyun,et al. Sustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2019,116(43):21732-21738.
APA Liu, Bin.,Zhang, Zhijian.,Hu, Yanyun.,Lu, Yan.,Li, Duanzhuo.,...&Li, Xiaoying.(2019).Sustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,116(43),21732-21738.
MLA Liu, Bin,et al."Sustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 116.43(2019):21732-21738.

入库方式： OAI收割

来源：上海药物研究所

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