Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, 20032 Shanghai, People's Republic of China.
Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Hubei Polytechnic University School of Medicine, 435003 Huangshi, Hubei, People's Republic of China.
Proc Natl Acad Sci U S A. 2019 Oct 22;116(43):21732-21738. doi: 10.1073/pnas.1907288116. Epub 2019 Oct 8.
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.
内质网（ER）应激在肥胖和 2 型糖尿病（T2DM）等代谢疾病中起着重要作用，尽管其潜在机制和调节途径仍有待阐明。在这里，我们在瘦鼠中诱导慢性低度 ER 应激，使其达到类似于高脂肪饮食（HFD）喂养肥胖鼠的水平，发现其通过增强肝糖异生导致高血糖。从机制上讲，持续的 ER 应激上调去泛素化酶泛素特异性肽酶 14（USP14），从而增加 3'，5'-环单磷酸反应元件结合蛋白（CREB）蛋白（CBP）的稳定性和水平，以增强胰高血糖素的作用和肝糖异生。USP14 在肝脏中的过表达可显著增加肝葡萄糖输出。与此一致的是，肝特异性敲低 USP14 可消除 ER 应激对葡萄糖代谢的影响，并改善肥胖鼠的高血糖和葡萄糖耐量。总之，我们的研究结果表明了 ER 应激诱导的葡萄糖稳态破坏的机制，并提出 USP14 是治疗 T2DM 的潜在治疗靶点。
