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Updated: Jun 1, 2025

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method
Published on: October 23, 2018
Proline exacerbates hepatic gluconeogenesis via paraspeckle-dependent mRNA retention
Yurong Zhao1,2,3, Xinxin Chai1,2,3, Junxuan Peng1,2,3
1Institute of Environmental Medicine and Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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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