2. Academic Validation
  3. Proline exacerbates hepatic gluconeogenesis via paraspeckle-dependent mRNA retention

Proline exacerbates hepatic gluconeogenesis via paraspeckle-dependent mRNA retention

  • Nat Metab. 2025 Feb;7(2):367-382. doi: 10.1038/s42255-024-01206-5.
Yurong Zhao # 1 2 3,  Xinxin Chai # 1 2 3,  Junxuan Peng 1 2 3,  Yi Zhu 1 2 3,  Rong Dong 4,  Junwei He 5,  Linghao Xia 5,  Sishuo Liu 1 2 3,  Jingzhou Chen 1 2 3,  Zhengping Xu 1 2 3,  Chi Luo 6,  Jinghao Sheng 7 8 9
Affiliations

Affiliations

  • 1 Institute of Environmental Medicine and Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
  • 3 Cancer Center, Zhejiang University, Hangzhou, China.
  • 4 NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, China.
  • 5 College of Life Science, Zhejiang University, Hangzhou, China.
  • 6 Liangzhu Laboratory, Zhejiang University, Hangzhou, China. chi.luo@alumni.tufts.edu.
  • 7 Institute of Environmental Medicine and Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. jhsheng@zju.edu.cn.
  • 8 Liangzhu Laboratory, Zhejiang University, Hangzhou, China. jhsheng@zju.edu.cn.
  • 9 Cancer Center, Zhejiang University, Hangzhou, China. jhsheng@zju.edu.cn.
  • # Contributed equally.
PMID: 39820557 DOI: 10.1038/s42255-024-01206-5
Abstract

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.

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