SIRT1 relieves Necrotizing Enterocolitis through inactivation of Hypoxia-inducible factor (HIF)-1a

Abstract

Necrotizing enterocolitis (NEC) is a major cause of mortality and morbidity in newborns, characterized by inflammatory intestinal necrosis. Sirtuin-1 (SIRT1), a NAD-dependent deacetylase, is involved in multiple biological functions. It has been reported that SIRT1 was downregulated in NEC tissues. However, the precise role of SIRT1 in NEC progress remains unknown. In this study, we found that SIRT1 was decreased in serum samples of NEC patients, associated with an inflammation response. an in vitro model was established by using LPS-induced NEC-like cell in this study. The results indicate that overexpression of SIRT1 inhibited the cell apoptosis induced by LPS. Besides, overexpression of SIRT1 suppressed the high expression of proinflammatory factors (IL-6, IL-8, and TNF-α), the decrease of transepithelial electrical resistance (TEER), and the decline expression of tight junction proteins (ZO-1, ZO-2, and Claudin-4) induced by LPS in Caco-2 cells. What is more, serum HIF-1α was increased in NEC patients. SIRT1 overexpression suppressed the expression and activity of HIF-1a, while knockdown of SIRT1 made the opposite effect. In summary, this study indicates that overexpression of SIRT1 alleviates the inflammation response and intestinal epithelial barrier dysfunction through regulating the expression and inactivation of HIF-1a.

Regulation of SIRT1 and Its Roles in Inflammation

“…Furthermore, the direct deacetylation by SIRT1 on HIF1a is required for HIF1a protein stability during hypoxia (141). Consistently, SIRT1 suppresses the high expression of proinflammatory factors, including IL-6, IL-8, and TNF-a, and alleviates intestinal epithelia barrier dysfunction by hindering the expression and activity of HIF1a in necrotizing enterocolitis (142). Liu et al demonstrated that SIRT1-HIF1a signaling contributes to the prerequisite role of SIRT1 in orchestrating the balance between proinflammatory T helper type 1 cells and anti-inflammatory Foxp3 (+) regulatory T cells in dendritic cells (143).…”

Angiopoietin-2 silence alleviates lipopolysaccharide-induced inflammation, barrier dysfunction and endoplasmic reticulum stress of intestinal epithelial cells by blocking Notch signaling pathway

“…NEC is characterized by inflammation, and persistent inflammation can result in impaired intestinal barrier, allowing for bacterial translocation and promote the progression of disease [ 24 , 25 ]. It has been reported that overexpression of Sirtuin-1 relieves NEC by reducing the inflammatory response and intestinal epithelial barrier dysfunction [ 26 ]. Zhang D et al disclosed that milk fat globule membrane could alleviate NEC by suppressing LPS-induced inflammatory response in IEC-6 cells [ 27 ].…”

HIF-1α stabilization modified by glutaredoxin-1 is critical for intestinal angiogenesis in NEC pathogenesis

“…A study showed that dimethyloxalylglycine (DMOG), a prolyl hydroxylase (PHD) inhibitor, could stabilize HIF-1α then promote intestinal microvascular integrity through VEGF signaling [14]. Another research demonstrated that inactivation of HIF-1α by SIRT1 overexpression alleviates the inflammation associated intestinal epithelial damage [32]. Those studies show completely opposite results, may be due to different experimental methods.…”