Xu FZ, Dou L, Wu X, Xia CX, Yu DN, Man Y, Shen T, Huang XQ. Exosomal transfer of miR-375-3p from pancreatic β cells to hepatocytes impairs hepatic glycogenesis via Rbpj repression. World J Diabetes 2025; 16(10): 109815 [PMID: 41113486 DOI: 10.4239/wjd.v16.i10.109815]
Corresponding Author of This Article
Xiu-Qing Huang, PhD, The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, No. 1 Dahua Road, Dongdan, Dongcheng District, Beijing 100730, China. huang_xq118@126.com
Research Domain of This Article
Cell Biology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Diabetes. Oct 15, 2025; 16(10): 109815 Published online Oct 15, 2025. doi: 10.4239/wjd.v16.i10.109815
Exosomal transfer of miR-375-3p from pancreatic β cells to hepatocytes impairs hepatic glycogenesis via Rbpj repression
Fang-Zhi Xu, Lin Dou, Xi Wu, Chen-Xi Xia, Dong-Ni Yu, Yong Man, Tao Shen, Xiu-Qing Huang
Fang-Zhi Xu, Lin Dou, Xi Wu, Chen-Xi Xia, Dong-Ni Yu, Yong Man, Tao Shen, Xiu-Qing Huang, The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, Beijing 100730, China
Co-first authors: Fang-Zhi Xu and Lin Dou.
Author contributions: Huang XQ and Dou L conceptualized the study; Xu FZ, Wu X, Man Y and Shen T developed the methodology; Wu X and Xia CX performed data curation; Xu FZ and Huang XQ wrote the original draft; Dou L and Yu DN reviewed and edited the manuscript; Huang XQ was responsible for supervision and funding acquisition; All authors have read and approved the final manuscript.
Supported by Beijing Natural Science Foundation, No. 7252124; National High Level Hospital Clinical Research Funding, No. BJ-2024-219, No. BJ-2025-125 and No. BJ-2023-236; National Natural Science Foundation of China, No. 82370584, No. 82470395 and No. 81600618; and National Key R&D Program of China, No. 2021YFE0114200.
Institutional animal care and use committee statement: The protocols were approved by Laboratory Animal Welfare Ethics Branch of Biomedical Ethics Committee of Peking University (No. LA2022012) following the Guidelines for the Care and Use of Animals.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: Data will be made available on reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xiu-Qing Huang, PhD, The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, No. 1 Dahua Road, Dongdan, Dongcheng District, Beijing 100730, China. huang_xq118@126.com
Received: May 29, 2025 Revised: July 18, 2025 Accepted: September 5, 2025 Published online: October 15, 2025 Processing time: 139 Days and 7.5 Hours
Abstract
BACKGROUND
Glucotoxic pancreatic β cells impair glycogenesis of hepatocytes, with exosomes serving as novel mediators. miR-375-3p is the most abundant miRNA in the pancreas and critical for β-cell function, but whether it plays a role in pancreas-liver crosstalk remains unclear.
AIM
To investigate the role of miR-375-3p, a key regulator of pancreatic β cells, in remotely regulating hepatocyte glycogenesis via exosomes.
METHODS
Mice fed a high-fat diet (HFD) served as animal models, and mouse primary pancreatic islet cells and the β-cell line MIN-6 were used as cellular models. miR-375-3p expression in pancreatic cells, hepatocytes and exosomes was detected in both animal and cellular models. Transwell assays, exosome treatment, and exosome-depleted supernatant culture were used to investigate the role of exosomal miR-375-3p in pancreatic-hepatocyte crosstalk. The AKT/GSK signaling pathway and hepatic glycogen content were used as indicators to evaluate hepatocyte glycogenesis. Luciferase reporter assays were used to evaluate the downstream targets of miR-375-3p.
RESULTS
Increased levels of miR-375-3p were observed in both the pancreas and liver of HFD-fed mice. In contrast to the in vivo results, high-glucose treatment exclusively increased the expression of miR-375-3p in pancreatic cells but had no effect on hepatocytes. Furthermore, hepatocytes treated with the supernatant and exosomes from glucotoxic pancreatic cells presented elevated expression of miR-375-3p. Additionally, exosomal transfer of miR-375-3p from pancreatic cells to hepatocytes suppressed the AKT/GSK signaling pathway, thereby reducing the hepatic glycogen content. Luciferase analysis indicated that the recombination signal binding protein for the immunoglobulin kappa J region (Rbpj) is a target gene of miR-375-3p. Rbpj inhibition impaired hepatic glycogenesis, and Rbpj overexpression reversed the effect on glycogenesis induced by miR-375-3p.
CONCLUSION
Pancreatic cell-derived miR-375-3p can be delivered to hepatocytes via exosomes and inhibits hepatocyte glycogenesis by targeting Rbpj.
Core Tip: Glucotoxic pancreatic β cells impair glycogenesis of hepatocytes, with exosomes serving as novel mediators. Glucotoxicity increased the expression of miR-375-3p in pancreatic cells but had no effect on hepatocytes. Exosomal transfer of miR-375-3p from pancreatic β cells to hepatocytes enables it to directly target and inhibit the recombination signal binding protein for the immunoglobulin kappa J region (Rbpj). This suppression of Rbpj subsequently impairs the AKT/GSK-3 signaling pathway, thereby reducing hepatic glycogen content.
