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

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.
Mesh Terms:
Animals, Diabetes Mellitus, Type 2, Diet, High-Fat, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Gene Knockdown Techniques, Glucagon, Gluconeogenesis, Glucose, Glucose Intolerance, Hyperglycemia, Mice, Mice, Inbred C57BL, Mice, Obese, Obesity, Ubiquitin Thiolesterase
Proc. Natl. Acad. Sci. U.S.A.
Date: Dec. 22, 2018
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