Open AccessSustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14
Author(s) -
Bin Liu,
Zhijian Zhang,
Yanyun Hu,
Yan Lü,
Duanzhuo Li,
Jie Liu,
Shengjie Liao,
Min Hu,
Yuxing Wang,
Die Zhang,
Yulu Chen,
Qilan Qian,
Xianfeng Lv,
Duojiao Wu,
Minjia Tan,
Cheng Hu,
Xuelian Xiong,
Xiaoying Li
Publication year - 2019
Publication title -
proceedings of the national academy of sciences
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1907288116
Subject(s) - deubiquitinating enzyme , medicine , endocrinology , endoplasmic reticulum , unfolded protein response , gluconeogenesis , glucagon , creb , ubiquitin , biology , chemistry , insulin , metabolism , microbiology and biotechnology , biochemistry , gene , transcription factor
Significance Endoplasmic reticulum (ER) stress plays an important role in obesity and type 2 diabetes mellitus (T2DM), with controversy in mechanisms and regulatory pathways. We found that chronic low-grade ER stress in lean mice promoted hyperglycemia due to enhanced hepatic gluconeogenesis via ubiquitin-specific peptidase14 (USP14) induction, which, in turn, increased the stability of adenosine 3′,5′-cyclic monophosphate–responsive element binding protein to enhance glucagon action and hepatic gluconeogenesis. Overexpression of USP14 in the liver significantly increased hepatic glucose output. Liver-specific knockdown of USP14 abrogated the effects of ER stress on glucose metabolism, improved hyperglycemia and glucose intolerance in obese mice. Our findings show a mechanism underlying ER stress-induced disruption of glucose homeostasis, and present USP14 as a potential therapeutic target against T2DM.
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