Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Life Sci. 2021 Jul 1;276:119367. doi: 10.1016/j.lfs.2021.119367. Epub 2021 Mar 26.
Estrogen and its metabolites often lead to intrahepatic cholestasis in susceptible women with pregnancy, administration of oral contraceptives and postmenopausal hormone replacement therapy. Recently, dysfunction of the gut-liver axis has been suggested to play a pivotal role in the progression of cholestasis, but details about estrogen cholestasis (EC)-induced gut and liver injury are still largely unknown. This study aims to gain insight into EC-induced gut and liver injury and cell signaling implicated.
Male rats were exposed to 5 and 10 mg/kg of 17α-ethinylestradiol via subcutaneous injection for 5 successive days to simulate human EC.
By detection of these estrogen cholestatic rats, we found that EC induced inflammation in the liver but not in the intestine through activating NF-κB signaling pathway. EC strongly induced oxidative stress in both the liver and intestine, and activated the hepatic Nrf2/Gclm/Gclc pathway and the intestinal Nrf2/Ho-1 pathway, respectively, for adaptively regulating oxidative stress. EC increased cell apoptosis in both the liver and intestine. Additionally, EC elevated phosphorylation of Akt, ERK1/2, and p38 in the liver and increased phosphorylation of p38 in the intestine.
EC induces liver inflammation, both gut and liver oxidative stress and apoptosis, involving in activating PI3K/Akt and MAPK signaling pathways. Investigation of EC-induced gut and liver injury contributes to the development of new potential therapeutic strategies.
雌激素及其代谢物常导致易感妊娠、口服避孕药和绝经后激素替代治疗的女性发生肝内胆汁淤积。最近，肠-肝轴功能障碍被认为在胆汁淤积的进展中起关键作用，但关于雌激素性胆汁淤积（EC）引起的肠道和肝脏损伤的细节仍知之甚少。本研究旨在深入了解 EC 诱导的肠道和肝脏损伤及相关的细胞信号转导。
雄性大鼠通过皮下注射 17α-乙炔基雌二醇 5 和 10mg/kg，连续 5 天，模拟人类 EC。
通过检测这些雌激素性胆汁淤积大鼠，我们发现 EC 通过激活 NF-κB 信号通路在肝脏而非肠道中引起炎症。EC 强烈诱导肝脏和肠道的氧化应激，并分别激活肝 Nrf2/Gclm/Gclc 途径和肠 Nrf2/Ho-1 途径，以适应调节氧化应激。EC 增加了肝脏和肠道的细胞凋亡。此外，EC 增加了肝脏中 Akt、ERK1/2 和 p38 的磷酸化，增加了肠道中 p38 的磷酸化。
EC 诱导肝脏炎症、肠道和肝脏氧化应激及细胞凋亡，涉及激活 PI3K/Akt 和 MAPK 信号通路。研究 EC 诱导的肠道和肝脏损伤有助于开发新的潜在治疗策略。
