High-fat diet aggravates colitis via mesenteric adipose tissue derived exosome metastasis-associated lung adenocarcinoma transcript 1

World J Gastroenterol. 2022 Aug 7;28(29):3838-3853. doi: 10.3748/wjg.v28.i29.3838.

Abstract

Background: Obesity is associated with an increased risk of developing Crohn's disease (CD), higher disease activity, and comparatively worse clinical outcomes.

Aim: To investigate the role of mesenteric adipose tissue-derived exosomes in the pathogenesis of CD aggravation in obese individuals.

Methods: First, we induced colitis in mice initiated on high-fat and normal diets and compared the severity of colitis. We then extracted and identified exosomes from mesenteric adipose tissue and determined the levels of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in mesenteric adipose tissue-derived exosomes and the colon. Next, we demonstrated an interaction between MALAT1 and the miR-15a-5p/activating transcription factor 6 (ATF6) axis. Finally, we explored the effects of mesenteric adipose tissue-derived exosomes extracted from mice fed a high-fat or normal diet on the severity of 2,4,6-trinitrobe-nzenesulfonic acid (TNBS)-induced colitis and ATF6-related endoplasmic reticulum stress pathways.

Results: High-fat diet was found to aggravate TNBS-induced colitis in mice. The expression of MALAT1 in mesenteric adipose tissue-derived exosomes of high-fat diet-fed mice increased. The increased expression of MALAT1 in colon tissue exacerbated TNBS-induced colitis and activated the ATF6 endoplasmic reticulum stress pathway. This effect was partially reversed by the reduced expression of MALAT1 and overexpression of miR-15a-5p.

Conclusion: Mesenteric adipose tissue-derived exosome-encapsulated long noncoding RNAs MALAT1 targets the colon and aggravates TNBS-induced colitis in obese mice, which may potentially act on the miR-15a-5p/ATF6 axis and activate endoplasmic reticulum stress.

Keywords: Colitis; Crohn’s disease; Inflammatory bowel disease; Mesenteric adipose tissue; Metastasis-associated lung adenocarcinoma transcript; Obesity; miR-15a-5p.

MeSH terms

  • Activating Transcription Factor 6
  • Adipose Tissue / metabolism
  • Animals
  • Colitis* / chemically induced
  • Colitis* / complications
  • Colitis* / genetics
  • Diet, High-Fat / adverse effects
  • Exosomes* / metabolism
  • Mice
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Obesity / metabolism
  • RNA, Long Noncoding* / metabolism

Substances

  • Activating Transcription Factor 6
  • Malat1 long non-coding RNA, mouse
  • MicroRNAs
  • RNA, Long Noncoding