Abstract
Sirtuin 6 (SIRT6), as a NAD + -dependent deacetylase, plays an indispensable role in the regulation of health and physiology. Loss of SIRT6 causes spontaneous colitis in mice and makes intestinal epithelial cells prone to stress. However, whether SIRT6 overexpression increases resistance to colitis remains unknown. Here, in vivo results demonstrated that SIRT6 overexpression attenuates DSS-induced colitis in terms of clinical manifestations, histopathological damage, loss of tight junction function and imbalanced intestinal microenvironment. Additionally, we also found that the activation of NF-κB and c-Jun induced by DSS is diminished by SIRT6 overexpression. Furthermore, SIRT6 may regulate TAK1 to inhibit NF-κB and c-Jun signaling. Thus, our findings highlight the protective effect of SIRT6 on colon, further supporting the perspective that SIRT6 may be a therapeutic target for intestine injury under stress.
Highlights
Sirtuin 6 (SIRT6), as an adenosine diphosphate (ADP)-ribosyl transferase and NAD + -dependent deacetylase, has been associated with metabolism, longevity regulation, and many other essential biological processes [1]
To study the protective capability of SIRT6, we induced a dextran sulfate sodium salt (DSS) colitis model in mice on day 1 according to the established protocol, with only minor modifications
The induction of colitis with DSS caused a significant loss of body weight after 7-day administration, and the weight loss began on day 3 of DSS treatment
Summary
SIRT6, as an adenosine diphosphate (ADP)-ribosyl transferase and NAD + -dependent deacetylase, has been associated with metabolism, longevity regulation, and many other essential biological processes [1]. SIRT6-deficient mice experience severe cellular and physiological inflammation, including type 1 interferon response, LINE 1 activation, and sterile inflammation [3]. In parallel, overexpressed SIRT6 is thought to ameliorate a variety of age-related disorders. Our previous studies showed that SIRT6 overexpression attenuates cisplatin-induced acute kidney injury, including inflammation and apoptosis, by inhibiting ERK1/2 signaling [4]. FY Liu reported that intestinal epithelial cell-specific knockout of SIRT6 increases susceptibility to dextran sulfate sodium salt (DSS)-induced colitis in mice. There is a decreased expression of colonic SIRT6 in both DSS-induced colitis mouse model and ulcerative colitis patients [5]. The effects of overexpressed SIRT6 on the colon have not yet been elucidated
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