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

World J Gastroenterol. 2019 Oct 14;25(38):5800-5813. doi: 10.3748/wjg.v25.i38.5800.


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.

Keywords: Apoptosis; Endoplasmic reticulum stress; Intestinal barrier; Sirtuin 1; Ulcerative colitis.

MeSH terms

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


  • 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