Published online Oct 14, 2019. doi: 10.3748/wjg.v25.i38.5800
Peer-review started: July 16, 2019
First decision: August 2, 2019
Revised: September 11, 2019
Accepted: September 13, 2019
Article in press: September 13, 2019
Published online: October 14, 2019
Ulcerative colitis (UC), the main subtype of inflammatory bowel disease (IBD), is a chronic relapsing inflammatory disorder of the large intestine. The incidence and prevalence of UC have increased in recent years. Sirtuin 1 (SIRT1), a member of the mammalian sirtuin family of proteins, is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase and plays an essential role in caloric restriction, life span modulation, and cell fate determination. Recently, a number of studies have demonstrated that SIRT1 plays a protective role in colitis.
Although a large number of therapeutic agents, including 5-ASA drugs, immunosuppressants, steroids, and emerging biological agents, have appeared in the past few years, most patients still experience severe complications or recurrence of the disease, which greatly reduces their quality of life.
To investigate the role of SIRT1 in intestinal epithelial cells in UC and further explore the underlying mechanisms.
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. Annexin V-APC/7-AAD assays were performed to evaluate Caco-2 apoptosis. DSS-induced colitis mice was 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.
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 rates (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.
SIRT1 activation contributes to enhanced intestinal barrier integrity and reduced apoptosis of intestinal epithelial cells via the suppression of endoplasmic reticulum (ER) stress-mediated apoptosis-associated molecules CHOP and caspase-12.
SIRT1 may serve as a novel drug target, and SIRT1 activation is a promising therapeutic strategy for UC.