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©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
High-fat diet aggravates colitis via mesenteric adipose tissue derived exosome metastasis-associated lung adenocarcinoma transcript 1
Dong Chen, Miao-Miao Lu, Jin-Hai Wang, Yue Ren, Ling-Ling Xu, Wei-Xin Cheng, Sai-Sai Wang, Xiao-Lin Li, Xiao-Fei Cheng, Jian-Guo Gao, Farhin Shaheed Kalyani, Xi Jin
Dong Chen, Jin-Hai Wang, Sai-Sai Wang, Xiao-Fei Cheng, Department of Colorectal Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Miao-Miao Lu, Yue Ren, Ling-Ling Xu, Wei-Xin Cheng, Farhin Shaheed Kalyani, Department of Medicine, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
Xiao-Lin Li, Department of Emergency, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Jian-Guo Gao, Xi Jin, Department of Gastroenterology, The First affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Author contributions: Jin X designed the report; Chen D performed experiments and statistical analysis; Lu MM wrote the paper and assisted to design the report; Wang JH, Ren Y, Wang SS, Xu LL, Cheng XF, Cheng WX, Gao JG, and Li XL assisted to perform experiments and analyzed data; Kalyani FS assisted with paper writing; all authors had access to the study data and reviewed and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81770574; and the Natural Science Foundation of Zhejiang Province, No. LZ21H030002 and No. LY21H030005.
Institutional animal care and use committee statement: The study was reviewed and approved by the institutional review board of the Tab of Animal Experimental Ethical Inspection of the First Affiliated Hospital of Zhejiang University, NO. 2020-1101.
Conflict-of-interest statement: There are no conflicts of interest to report.
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, Professor, Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China.
jxfl007@zju.edu.cn
Received: December 4, 2021
Peer-review started: December 4, 2021
First decision: April 16, 2022
Revised: April 28, 2022
Accepted: July 6, 2022
Article in press: July 6, 2022
Published online: August 7, 2022
Processing time: 242 Days and 1.6 Hours
ARTICLE HIGHLIGHTS
Research background
Obesity is associated with an increased risk of developing Crohn’s disease (CD), higher disease activity, and comparatively worse clinical outcomes, especially in CD patients with a high visceral adipose tissue ratio. However, the underlying mechanisms remain unclear.
Research motivation
Exosomes contain multiple non-coding RNAs such as long non-coding RNAs (lncRNAs), which serve as messengers in cell-cell communication. Visceral adipose tissue derived exosomes display tissue affinity and preferentially target the colonic lamina propria. We hypothesized that obesity exacerbates inflammatory bowel disease, partially through mesenteric adipose tissue-derived exosomes.
Research objectives
To investigate the role of mesenteric adipose tissue-derived exosomes in CD aggravation through obesity, thereby providing a potential therapeutic target for CD in this subpopulation.
Research methods
A 2,4,6-trinitrobe-nzenesulfonic acid (TNBS) was used to induce colitis in mice fed a high-fat diet (HFD) and normal diet (ND). Exosomes from the mesenteric adipose tissue were extracted and identified, followed by the investigation of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression. Luciferase reporter and RNA pull-down assays were performed to verify the interaction between MALAT1 and miR-15a-5p/activating transcription factor 6 (ATF6) axis. Finally, mesenteric adipose tissue-derived exosomes extracted from HFD-fed mice were isolated and treated with either a short hairpin RNA targeting MALAT1 (shMALAT) or an miR-15a-5p mimic before being injected into mice to explore their influence on TNBS-induced colitis.
Research results
HFD can aggravate TNBS-induced colitis in mice, and increase the expression of MALAT1 in mesenteric adipose tissue-derived exosomes. Increased expression of MALAT1 in the colon tissue exacerbated TNBS-induced colitis and activated the ATF6-related endoplasmic reticulum stress pathway. Moreover, this effect was partially reversed by the reduced expression of MALAT1 and overexpression of miR-15a-5p.
Research conclusions
Mesenteric adipose tissue-derived exosome-encapsulated lncRNA MALAT1 targets the colon and aggravates TNBS-induced colitis in obese mice, which may potentially act on the miR-15a-5p/ATF6 axis and indice endoplasmic reticulum stress.
Research perspectives
Obesity-mediated aggravation of colitis might involve the mesenteric adipose tissue-derived exosome lncRNA MALAT1, but the specific cells of the intestine targeted by MALAT1 deserve further exploration.
