Sirtuin 1 alleviates endoplasmic reticulum stress-mediated apoptosis of intestinal epithelial cells in ulcerative colitis.

Abstract

BACKGROUND:

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase that is involved in various diseases, including cancers, metabolic diseases, and inflammation-associated diseases. However, the role of SIRT1 in ulcerative colitis (UC) is still confusing.

AIM:

To investigate the role of SIRT1 in intestinal epithelial cells (IECs) in UC and further explore the underlying mechanisms.

METHODS:

We developed a coculture model using macrophages and Caco-2 cells. After treatment with the SIRT1 activator SRT1720 or inhibitor nicotinamide (NAM), the expression of occludin and zona occludens 1 (ZO-1) was assessed by Western blot analysis. Annexin V-APC/7-AAD assays were performed to evaluate Caco-2 apoptosis. Dextran sodium sulfate (DSS)-induced colitis mice were exposed to SRT1720 or NAM for 7 d. Transferase-mediated dUTP nick-end labeling (TUNEL) assays were conducted to assess apoptosis in colon tissues. The expression levels of glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, caspase-9, and caspase-3 in Caco-2 cells and the colon tissues of treated mice were examined by quantitative real-time PCR and Western blot.

RESULTS:

SRT1720 treatment increased the protein levels of occludin and ZO-1 and inhibited Caco-2 apoptosis, whereas NAM administration caused the opposite effects. DSS-induced colitis mice treated with SRT1720 had a lower disease activity index (P < 0.01), histological score (P < 0.001), inflammatory cytokine levels (P < 0.01), and apoptotic cell rate (P < 0.01), while exposure to NAM caused the opposite effects. Moreover, SIRT1 activation reduced the expression levels of GRP78, CHOP, cleaved caspase-12, cleaved caspase-9, and cleaved caspase-3 in Caco-2 cells and the colon tissues of treated mice.

CONCLUSION:

SIRT1 activation reduces apoptosis of IECs via the suppression of endoplasmic reticulum stress-mediated apoptosis-associated molecules CHOP and caspase-12. SIRT1 activation may be a potential therapeutic strategy for UC.

• Authors: Meng-Ting Ren, Meng-Li Gu, Xin-Xin Zhou, Mo-Sang Yu, Hang-Hai Pan, Feng Ji, Chen-Yan Ding
• Journal: World journal of gastroenterology (World J Gastroenterol) Vol. 25 Issue 38 Pg. 5800-5813 (Oct 14 2019) ISSN: 2219-2840 [Electronic] United States
• PMID: 31636473 (Publication Type: Journal Article)
• Copyright: ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.

Chemical References

• DDIT3 protein, human
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Heterocyclic Compounds, 4 or More Rings
• Hspa5 protein, mouse
• SRT1720
• Transcription Factor CHOP
• Niacinamide
• Dextran Sulfate
• CASP12 protein, human
• Casp12 protein, mouse
• Caspase 12
• SIRT1 protein, human
• Sirt1 protein, mouse
• Sirtuin 1

Topics

• Animals
• Apoptosis
• Caco-2 Cells
• Caspase 12 (metabolism)
• Coculture Techniques
• Colitis, Ulcerative (chemically induced, drug therapy, pathology)
• Dextran Sulfate (toxicity)
• Disease Models, Animal
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress
• Epithelial Cells (drug effects, pathology)
• Female
• Heterocyclic Compounds, 4 or More Rings (administration & dosage)
• Humans
• Intestinal Mucosa (cytology, pathology)
• Macrophages
• Mice
• Niacinamide (administration & dosage)
• Sirtuin 1 (antagonists & inhibitors, metabolism)
• Transcription Factor CHOP (metabolism)