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Proline exacerbates hepatic gluconeogenesis via paraspeckle-dependent mRNA retention
Nature Metabolism ( IF 18.9 ) Pub Date : 2025-01-16 , DOI: 10.1038/s42255-024-01206-5
Yurong Zhao, Xinxin Chai, Junxuan Peng, Yi Zhu, Rong Dong, Junwei He, Linghao Xia, Sishuo Liu, Jingzhou Chen, Zhengping Xu, Chi Luo, Jinghao Sheng

Type 2 diabetes (T2D) is a global health issue characterized by abnormal blood glucose levels and is often associated with excessive hepatic gluconeogenesis. Increased circulating non-essential amino acids (NEAAs) are consistently observed in individuals with T2D; however, the specific contribution of each amino acid to T2D pathogenesis remains less understood. Here, we report an unexpected role of the NEAA proline in coordinating hepatic glucose metabolism by modulating paraspeckle, a nuclear structure scaffolded by the long non-coding RNA Neat1. Mechanistically, proline diminished paraspeckles in hepatocytes, liberating the retained mRNA species into cytoplasm for translation, including the mRNAs of Ppargc1a and Foxo1, contributing to enhanced gluconeogenesis and hyperglycaemia. We further demonstrated that the proline–paraspeckle–mRNA retention axis existed in diabetic liver samples, and intervening in this axis via paraspeckle restoration substantially alleviated hyperglycaemia in both female and male diabetic mouse models. Collectively, our results not only delineated a previously unappreciated proline-instigated, paraspeckle-dependent mRNA-retention mechanism regulating gluconeogenesis, but also spotlighted proline and paraspeckle as potential targets for managing hyperglycaemia.



中文翻译:


脯氨酸通过副斑依赖性 mRNA 保留加剧肝脏糖异生



2 型糖尿病 (T2D) 是一个全球性的健康问题,其特征是血糖水平异常,通常与肝脏糖异生过度有关。在 T2D 患者中始终观察到循环非必需氨基酸 (NEAA) 增加;然而,每种氨基酸对 T2D 发病机制的具体贡献仍然不太清楚。在这里,我们报道了 NEAA 脯氨酸通过调节副斑在协调肝脏葡萄糖代谢中的意想不到的作用,副斑是由长非编码 RNA Neat1 支撑的核结构。从机制上讲,脯氨酸减少了肝细胞中的副斑点,将保留的 mRNA 物种释放到细胞质中进行翻译,包括 Ppargc1aFoxo1 的 mRNA,导致糖异生增强和高血糖。我们进一步证明,糖尿病肝脏样本中存在脯氨酸-副斑点-mRNA 保留轴,通过副斑恢复干预该轴可显着缓解雌性和雄性糖尿病小鼠模型的高血糖。总的来说,我们的结果不仅描绘了以前未被重视的脯氨酸诱导的、副斑依赖性 mRNA 保留机制来调节糖异生,而且还突出了脯氨酸和副斑是控制高血糖的潜在靶点。

更新日期:2025-01-16
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