PUBLICATION
27-Hydroxycholesterol activates the GSK-3β/β-catenin signaling pathway resulting in intestinal fibrosis by inducing oxidative stress: effect of dietary interventions
- Authors
- Xiao, W., Hu, C., Ni, Y., Wang, J., Jiao, K., Zhou, M., Li, Z.
- ID
- ZDB-PUB-240107-17
- Date
- 2024
- Source
- Inflammation research : official journal of the European Histamine Research Society ... [et al.] 73(2): 289-304 (Journal)
- Registered Authors
- Keywords
- 27-Hydroxycholesterol, Glycogen synthesis kinase-3?/?-catenin signaling pathway, Intestinal fibrosis
- MeSH Terms
-
- Inflammatory Bowel Diseases*
- Caco-2 Cells
- Proto-Oncogene Proteins c-akt/metabolism
- Zebrafish/metabolism
- Glycogen Synthase Kinase 3 beta/metabolism
- Epithelial-Mesenchymal Transition
- beta Catenin*/metabolism
- Fibrosis
- Signal Transduction
- Animals
- Humans
- Hydroxycholesterols/pharmacology
- Inflammation
- Oxidative Stress
- PubMed
- 38184500 Full text @ Inflamm. Res.
Citation
Xiao, W., Hu, C., Ni, Y., Wang, J., Jiao, K., Zhou, M., Li, Z. (2024) 27-Hydroxycholesterol activates the GSK-3β/β-catenin signaling pathway resulting in intestinal fibrosis by inducing oxidative stress: effect of dietary interventions. Inflammation research : official journal of the European Histamine Research Society ... [et al.]. 73(2):289-304.
Abstract
Objective Intestinal fibrosis, a common and serious complication of inflammatory bowel disease (IBD), results from chronic inflammation. A high-cholesterol diet may be a risk factor for IBD and 27-hydroxylcholesterol (27HC) is the main human cholesterol metabolite. This study investigated whether 27HC can induce intestinal fibrosis.
Methods The effects of cholesterol and 27HC on intestinal fibrosis were assessed in zebrafish and human intestinal epithelial Caco-2 cells.
Results Cholesterol and 27HC induced intestinal inflammation and collagen deposition, inhibited E-cadherin (E-ca) expression in the intestinal epithelium, and promoted nuclear translocation of β-catenin in zebrafish. Cholesterol and 27HC up-regulated expression of COL-1, α-SMA, CTGF, TIMP1, N-cadherin, vimentin, glycogen synthesis kinase-3β (GSK-3β) and β-catenin, but inhibited E-ca, in Caco-2 cells. The expression of these proteins was inhibited by CYP27A1 knockdown and β-catenin knockdown. 27HC-induced nuclear translocation of β-catenin occurs in Caco-2 cells. p38, ERK, and AKT activate β-catenin and thereby participate in 27HC-induced epithelia-mesenchymal transition (EMT) and fibrosis. 27HC-increased oxidative stress and the fibrosis and EMT markers, the nuclear translocation of β-catenin, and the up-regulation of p-cell kinase proteins promoted by 27HC were inhibited by N-acetyl-L-cysteine (NAC). Folic acid (FA), resveratrol (RES), and NAC all ameliorated the 27HC-induced effects in Caco-2 cells and zebrafish.
Conclusion A high-cholesterol diet caused intestinal fibrosis in zebrafish, mediated by a major cholesterol metabolite, 27HC. 27HC increased oxidative stress and activated p38, ERK, AKT, and β-catenin, leading to EMT of epithelial cells and intestinal fibrosis. FA and RES both ameliorated intestinal fibrosis by restraining 27HC-induced β-catenin activation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping