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Lack of intestinal Mucin-1 impairs intestinal epithelial barrier and promotes metabolic dysfunction-associated steatotic liver disease in male mice

Li, Zecheng ; Gu, Runchuan LU orcid ; Liu, Donghai ; Zhang, Yijia ; Qin, Yijin ; Li, Xinyu ; Qiao, Yuan ; Li, Ziyao ; Guo, Jing and Wang, Jun , et al. (2025) In Nature Communications 17(1).
Abstract

Accumulating evidence suggests that a compromised intestinal epithelial barrier (IEB) contributes to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD); however, the exact mechanisms remain unclear. Here we reveal that intestinal mucin 1 (MUC1) levels and glycosylation are decreased in both humans and male mice with MASLD. Enterocyte-specific Muc1 knockout aggravates high-fat diet (HFD)-induced IEB impairment and MASLD progression in male mice. Mechanistically, HFD feeding reduces the glycosylation of intestinal epithelial MUC1, triggering its clathrin-mediated endocytosis and NEDD4-mediated lysosomal degradation, which subsequently induces β-Catenin degradation and ultimately impaires the IEB. Notably,... (More)

Accumulating evidence suggests that a compromised intestinal epithelial barrier (IEB) contributes to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD); however, the exact mechanisms remain unclear. Here we reveal that intestinal mucin 1 (MUC1) levels and glycosylation are decreased in both humans and male mice with MASLD. Enterocyte-specific Muc1 knockout aggravates high-fat diet (HFD)-induced IEB impairment and MASLD progression in male mice. Mechanistically, HFD feeding reduces the glycosylation of intestinal epithelial MUC1, triggering its clathrin-mediated endocytosis and NEDD4-mediated lysosomal degradation, which subsequently induces β-Catenin degradation and ultimately impaires the IEB. Notably, enterocyte-specific overexpression of cytoplasmic-tail-deleted MUC1 protects against IEB impairment and mitigates MASLD progression. These findings indicate that reduced intestinal epithelial MUC1 levels facilitate the progression of MASLD. Preserving the glycosylation and levels of intestinal MUC1 to maintain IEB integrity is a potential therapeutic strategy to explore for MASLD.

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Contribution to journal
publication status
published
subject
in
Nature Communications
volume
17
issue
1
article number
321
publisher
Nature Publishing Group
external identifiers
  • scopus:105026931232
  • pmid:41350285
ISSN
2041-1723
DOI
10.1038/s41467-025-67034-7
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2025.
id
05bf21fe-28f1-41db-a862-2844c3331dc7
date added to LUP
2026-03-09 16:26:20
date last changed
2026-08-26 17:59:25
@article{05bf21fe-28f1-41db-a862-2844c3331dc7,
  abstract     = {{<p>Accumulating evidence suggests that a compromised intestinal epithelial barrier (IEB) contributes to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD); however, the exact mechanisms remain unclear. Here we reveal that intestinal mucin 1 (MUC1) levels and glycosylation are decreased in both humans and male mice with MASLD. Enterocyte-specific Muc1 knockout aggravates high-fat diet (HFD)-induced IEB impairment and MASLD progression in male mice. Mechanistically, HFD feeding reduces the glycosylation of intestinal epithelial MUC1, triggering its clathrin-mediated endocytosis and NEDD4-mediated lysosomal degradation, which subsequently induces β-Catenin degradation and ultimately impaires the IEB. Notably, enterocyte-specific overexpression of cytoplasmic-tail-deleted MUC1 protects against IEB impairment and mitigates MASLD progression. These findings indicate that reduced intestinal epithelial MUC1 levels facilitate the progression of MASLD. Preserving the glycosylation and levels of intestinal MUC1 to maintain IEB integrity is a potential therapeutic strategy to explore for MASLD.</p>}},
  author       = {{Li, Zecheng and Gu, Runchuan and Liu, Donghai and Zhang, Yijia and Qin, Yijin and Li, Xinyu and Qiao, Yuan and Li, Ziyao and Guo, Jing and Wang, Jun and Meng, Hua and Peng, Liang}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Lack of intestinal Mucin-1 impairs intestinal epithelial barrier and promotes metabolic dysfunction-associated steatotic liver disease in male mice}},
  url          = {{http://dx.doi.org/10.1038/s41467-025-67034-7}},
  doi          = {{10.1038/s41467-025-67034-7}},
  volume       = {{17}},
  year         = {{2025}},
}