P0141 Estrogen receptor β alleviates colitis in intestinal epithelial cells by activating HIF-1α and ATG-9a mediated autophagy

Abstract Background Ulcerative colitis (UC) manifests as excessive inflammation and compromised integrity of the intestinal epithelial barrier. Estrogen receptor β (ERβ) exerts anti-inflammatory effects in the colon. However, the mechanism remains unclear. This study aims to explore the role and mechanism of ERβ in alleviating colitis, and provide a novel therapeutic target for UC. Methods The level of ERβ and autophagy in the inflammatory and non-inflammatory colons of patients with UC were assessed. Mice with dextran sulfate sodium (DSS)-induced colitis were used to establish an in vivo model. The body weight change, colon length, disease activity index (DAI) and histological score of mice in each group were compared. In vitro, HT-29 cell inflammation was induced by lipopolysaccharide (LPS). ERB041, an ERβ specific agonist, was administered to DSS-induced mice and LPS-induced HT-29 cells. Autophagy in vivo and in vitro was evaluated by western blot, transmission electron microscope, and immunofluorescence. Co-immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assay were conducted to further delineate the mechanism between ERβ and autophagy. Results Compared with non-inflammatory mucosa, the expression of ERβ in the inflammatory mucosa in patients with UC was down-regulated, with autophagy inhibited significantly. ERβ activation attenuated the intestinal epithelial barrier disruption, decreased the level of pro-inflammatory cytokines, and significantly attenuated DSS-induced experimental colitis. Mechanically, ERB041 intervention activated autophagy, which was manifested as up-regulation of LC3BII expression, decreased p62 level and increased number of autolysosomes. ERβ interacted with hypoxia-inducible factor 1α (HIF-1α) and activated autophagy. Furthermore, HIF-1α bound to the promoter region of ATG- 9a, and positively regulates its transcription. Conclusion ERβ exerts anti-inflammatory effect by up-regulating HIF-1α and activating ATG-9a mediated autophagy in intestinal epithelial cells, and may be a promising therapeutic target for UC.