The DOI matches its Crossref record; 37 of the 38 references it cites were found in a registry or an index.
Cellular zinc is required for intestinal epithelial barrier maintenance via the regulation of claudin-3 and occludin expression
Open accessAbstract
Intracellular zinc is required for a variety of cell functions, but its precise roles in the maintenance of the intestinal tight junction (TJ) barrier remain unclear. The present study investigated the essential roles of intracellular zinc in the preservation of intestinal TJ integrity and the underlying molecular mechanisms. Depletion of intracellular zinc in both intestinal Caco-2 cells and mouse colons through the application of a cell-permeable zinc chelator N, N, N′, N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) induced a disruption of the TJ barrier, as indicated by increased FITC-labeled dextran flux and decreased transepithelial electrical resistance. The TPEN-induced TJ disruption is associated with downregulation of two TJ proteins, occludin and claudin-3. Biotinylation of cell surface proteins revealed that the zinc depletion induced the proteolysis of occludin but not claudin-3. Occludin proteolysis was sensitive to the inhibition of calpain activity, and increased calpain activity was observed in the zinc-depleted cells. Although quantitative PCR analysis and promoter reporter assay have demonstrated that the zinc depletion-induced claudin-3 downregulation occurred at transcriptional levels, a site-directed mutation in the egr1 binding site in the claudin-3 promoter sequence induced loss of both the basal promoter activity and the TPEN-induced decreases. Reduced egr1 expression by a specific siRNA also inhibited claudin-3 expression and transepithelial electrical resistance maintenance in cells. This study shows that intracellular zinc has an essential role in the maintenance of the intestinal epithelial TJ barrier through regulation of occludin proteolysis and claudin-3 transcription.
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“Zinc strengthens tight junctions through regulation of occludin proteolysis and claudin-3 transcription [290], increases mucus production, and reduces gastric acid secretion [184,291,292], while also promoting wound healing [293].”
From Nutritional Approaches to Enhance GLP-1 Analogue Therapy in Obesity: A Narrative Review (2025) · cites this paper as [293]
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Cites
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Piezo1 Regulates ZnT1-Mediated Zinc Homeostasis in Ulcerative Colitis
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InfluentialGut microbiota–mitochondria–barrier–multiorgan axis: a network-based hypothesis for systemic injury
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Eggshell Membrane in Gut Health: Processing-Dependent Redox, Barrier, Immune, and Microbiome Effects
Çakır, A., Ahmed, T. A., & Hincke, M. T. (2026) · Foods · doi:10.3390/foods15203673
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Metadata
- Authors
- Miyoshi, Y., Tanabe, S., & Suzuki, T.
- Affiliations
- Hiroshima University (JP)
- Corresponding author
- Suzuki, Takuya
- ORCID
- Suzuki, Takuya
- Venue
- American Journal of Physiology-Gastrointestinal and Liver Physiology
- Publisher
- American Physiological Society
- Published
- 2016-07-01
- Volume
- 311
- Issue
- 1
- Pages
- G105-G116
- ISSN
- 0193-1857 (ISSN-L)
- 1522-1547
- OpenAlex
- W2345985582
- Cited by
- 115
- References
- 38
- Citations by year
- 2026: 12 · 2025: 9 · 2024: 16 · 2023: 9 · 2022: 18 · 2021: 17 · 2020: 9 · 2019: 9 · 2018: 6 · 2017: 9 · 2016: 1
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- the Salt Science Research Foundation
- the Skylark Food Science Institute
- the Towa Foundation for Food Science & Research
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
- Keywords
- intracellular zinc, claudin-3, occludin, calpain, transepithelial electrical resistance, intestinal epithelium, tight junction integrity
- MeSH terms
- Animals, Binding Sites, Chelating Agents, Colon, Epithelial Cells, Humans, Intestinal Mucosa, Male, Mice, Inbred ICR, Permeability, Promoter Regions, Genetic, Transcription, Genetic, Transfection, Zinc, Signal Transduction, Electric Impedance, Caco-2 Cells, Tight Junctions, Zinc Sulfate, RNA Interference, Early Growth Response Protein 1, Proteolysis, Claudin-3, Occludin
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