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

doi:10.1073/pnas.1907288116

	Sustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14
	Liu, Bin 6,7; Zhang, Zhijian 5; Hu, Yanyun 5; Lu, Yan 4,7; Li, Duanzhuo 6; Liu, Jie 6; Liao, Shengjie 6; Hu, Min 6; Wang, Yuxing 6; Zhang, Die 6
刊名	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
	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
DOI	10.1073/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.
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关键词	ENDOPLASMIC-RETICULUM STRESS ; UNFOLDED PROTEIN RESPONSE ; HEPATIC GLUCOSE-METABOLISM ; INSULIN-RESISTANCE ; CREB ; PHOSPHORYLATION ; GLUCONEOGENESIS ; HOMEOSTASIS ; OBESITY ; ACTIVATION
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATL ACAD SCIENCES
WOS记录号	WOS:000491366700058
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/282679]
专题	中国科学院上海药物研究所
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.