Uncovering the Novel Role of NR1D1 in Regulating BNIP3-Mediated Mitophagy in Ulcerative Colitis

Background: Ulcerative colitis (UC) is a chronic, incurable condition characterized by mucosal inflammation and intestinal epithelial cell (IEC) damage. The circadian clock gene NR1D1, implicated in UC and the critical mitophagy process for epithelial repair, needs further exploration regarding its...

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Bibliographic Details
Published in:International journal of molecular sciences 2023-09, Vol.24 (18), p.14222
Main Authors: Chen, Yidong, Li, Junrong, Li, Shuang, Cheng, Yiyu, Fu, Xiaoyu, Li, Jiamin, Zhu, Liangru
Format: Article
Language:English
Subjects:
Analysis
Antigens
Apoptosis
Autophagy
BNIP3
Chromatin
circadian clock
Circadian rhythm
Dextran
Disease
Gene expression
Genes
Health aspects
Homeostasis
Inflammation
Inflammatory bowel disease
Metabolism
Microorganisms
Mitochondria
mitophagy
NR1D1
Pathogenesis
Pathophysiology
Proteins
Quality control
Reactive oxygen species
RNA sequencing
Signal transduction
Ulcerative colitis
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Summary:Background: Ulcerative colitis (UC) is a chronic, incurable condition characterized by mucosal inflammation and intestinal epithelial cell (IEC) damage. The circadian clock gene NR1D1, implicated in UC and the critical mitophagy process for epithelial repair, needs further exploration regarding its role in mitophagy regulation in UC. Methods: We created a jet lag mouse model and induced colitis with dextran sulfate sodium (DSS), investigating NR1D1’s role. Intestinal-specific Nr1d1 knockout mice were also generated. RNA sequencing, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays helped ascertain NR1D1’s regulatory effect on BNIP3 expression. The mitochondrial state in IECs was assessed through transmission electron microscopy, while confocal microscopy evaluated mitophagy-associated protein expression in colon tissue and CCD841 cells. Cell apoptosis and reactive oxygen species (ROS) were measured via flow cytometry. Results: We observed reduced NR1D1 expression in the IECs of UC patients, accentuated under jet lag and DSS exposure in mice. NR1D1 ablation led to disrupted immune homeostasis and declined mitophagy in IECs. NR1D1, usually a transcriptional repressor, was a positive regulator of BNIP3 expression, leading to impaired mitophagy, cellular inflammation, and apoptosis. Administering the NR1D1 agonist SR9009 ameliorated colitis symptoms, primarily by rectifying defective mitophagy. Conclusions: Our results suggest that NR1D1 bridges the circadian clock and UC, controlling BNIP3-mediated mitophagy and representing a potential therapeutic target. Its agonist, SR9009, shows promise in UC symptom alleviation.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms241814222