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©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
Antagonizing adipose tissue-derived exosome miR-103-hepatocyte phosphatase and tensin homolog pathway alleviates autophagy in non-alcoholic steatohepatitis: A trans-cellular crosstalk
Miao-Miao Lu, Yue Ren, Yu-Wei Zhou, Ling-Ling Xu, Meng-Meng Zhang, Lin-Ping Ding, Wei-Xin Cheng, Xi Jin
Miao-Miao Lu, Endoscopy Center, Children’s Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
Yue Ren, Yu-Wei Zhou, Lin-Ping Ding, Wei-Xin Cheng, Department of Medicine, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
Ling-Ling Xu, Department of Gastroenterology, The Second People’s Hospital of Yuhang District, Hangzhou 310003, Zhejiang Province, China
Meng-Meng Zhang, Department of Gastroenterology, Hangzhou Shangcheng District People’s Hospital, Hangzhou 310003, Zhejiang Province, China
Xi Jin, Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
Author contributions: Jin X designed the report; Lu MM performed experiments, wrote the paper and assisted to design the report; Ren Y and Zhou YW performed experiments and statistical analysis; Zhang MM, Ding LP, and Cheng WX assisted to perform experiments and analyzed data; and all authors had access to the study data and reviewed and approved the final manuscript.
Supported by the Natural Science Foundation of Zhejiang Province, No. LZ21H030002.
Institutional animal care and use committee statement: This study was carried out following the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institute of Health. The animal protocol was approved by the institutional review board of the Tab of Animal Experimental Ethical Inspection of the First Affiliated Hospital of Zhejiang University. The Reference Number is 2020-1407.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: All the data included in this study are available upon request by contact with the corresponding author.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Xi Jin, MD, PhD, Doctor, Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China. jxfl007@zju.edu.cn
Received: April 5, 2023
Peer-review started: April 5, 2023
First decision: May 23, 2023
Revised: June 11, 2023
Accepted: July 4, 2023
Article in press: July 4, 2023
Published online: August 7, 2023
BACKGROUND
Obesity plays a vital role in the occurrence and development of non-alcoholic steatohepatitis (NASH). However, the underlining mechanism is still unclear, where adipose tissue (AT) derived exosomes may actively participate. MicroRNAs (miRNAs) are commonly secreted from exosomes for cell communication. Though the regulation of miR-103 on insulin sensitivity has been reported, the specific role of AT-derived exosomes miR-103 in NASH is still vague and further investigation may provide novel therapeutic choices.
AIM
To determine the specific role of AT-derived exosomes miR-103 in developing NASH through various methods.
METHODS
The expression levels of miR-103 in the AT-derived exosomes and livers were detected and compared between NASH mice and control. The effect of miR-103 on NASH progression was also explored by antagonizing miR-103, including steatosis and inflammation degree changes. The interaction between miR-103 and the autophagy-related gene phosphatase and tensin homolog (PTEN) was confirmed by dual-luciferase reporter assay. The role of the interaction between miR-103 and PTEN on autophagy was verified in NASH-like cells. Finally, the effects of miR-103 from adipose-derived exosomes on NASH and autophagy were analyzed through animal experiments.
RESULTS
The expression of miR-103 was increased in NASH mice, compared to the control, and inhibition of miR-103 could alleviate NASH. The results of the dual-luciferase reporter assay showed miR-103 could interact with PTEN. MiR-103-anta decreased p-AMPKa, p-mammalian target of rapamycin (mTOR), and p62 but increased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in NASH mice. Similar results were also observed in NASH-like cells, and further experiments showed PTEN silencing inhibited the effect of miR-103-anta. AT derived-exosome miR-103 aggravated NASH and increased the expressions of p-AMPKa, p-mTOR, and p62 but decreased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in mice.
CONCLUSION
AT derived-exosome increased the levels of miR-103 in the liver, and miR-103 aggravated NASH. Mechanically, miR-103 could interact with PTEN and inhibit autophagy.
Core Tip: Our study confirms the important role of miR-103-phosphatase and tensin homolog-autophagy axis in the pathogenesis of non-alcoholic steatohepatitis (NASH). More importantly, the elevation of miR-103 in the liver of NASH mice is partly due to adipose tissue exosome secretion and integration, which also partially explains the mechanism of obesity leading to NASH.
