1,25(OH)2D3 alleviates oxidative stress and inflammation through up-regulating HMGCS2 in DSS-induced colitis

Background: Previous study found that supplements with active vitamin D3 alleviated experimental colitis. The objective of this study was to investigate the possible role of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a ketone synthase, on vitamin D3 protecting against experimental colitis.Methods: HMGCS2 and vitamin D receptor (VDR) were measured in UC patients. The effects of vitamin D deficiency (VDD) and exogenous 1,25(OH)2D3 supplementation on experimental colitis were investigated in dextran sulfate sodium (DSS)-treated mice. DSS-induced oxidative stress and inflammation were analyzed in HT-29 cells. HMGCS2 was detected in 1,25(OH)2D3-pretreated HT-29 cells and mouse intestines. HMGCS2 was silenced to investigate the role of HMGCS2 in 1,25(OH)2D3 protecting against experimental colitis.Results: Intestinal HMGCS2 downregulation was positively correlated with VDR reduction in UC patients. The in vivo experiments showed that VDD exacerbated DSS-induced colitis. By contrast, 1,25(OH)2D3 supplementation ameliorated DSS-induced colon damage, oxidative stress and inflammation. HMGCS2 was up-regulated after 1,25 (OH)2D3 supplementation both in vivo and in vitro. Transfection with HMGCS2-siRNA inhibited antioxidant and anti-inflammatory effects of 1,25(OH)2D3 in DSS-treated HT-29 cells.Conclusion: 1,25(OH)2D3 supplementation up-regulates HMGCS2, which is responsible for 1,25(OH)2D3-mediated protection against oxidative stress and inflammation in DSS-induced colitis. These findings provide a potential therapeutic strategy for alleviating colitis-associated oxidative stress and inflammation.