4.7 Article

Estrogen cholestasis induces gut and liver injury in rats involving in activating PI3K/Akt and MAPK signaling pathways

期刊

LIFE SCIENCES
卷 276, 期 -, 页码 -

出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2021.119367

关键词

Estrogen cholestasis; Gut-liver injury; Nrf2; MAPK pathway; PI3K; Akt pathway

资金

  1. National Natural Science Foundation of China [81803798, 82073939, 81573788]
  2. Tongji Hospital Fund [2019A08]

向作者/读者索取更多资源

Estrogen cholestasis induces liver inflammation and oxidative stress, while also increasing cell apoptosis in both the liver and intestine. It activates the NF-κB signaling pathway in the liver, and PI3K/Akt and MAPK signaling pathways in both gut and liver. Understanding EC-induced gut and liver injury may help in developing new therapeutic strategies.
Backgrounds: 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. Methods: Male rats were exposed to 5 and 10 mg/kg of 17?-ethinylestradiol via subcutaneous injection for 5 successive days to simulate human EC. Results: By detection of these estrogen cholestatic rats, we found that EC induced inflammation in the liver but not in the intestine through activating NF-?B 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. Conclusions: 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.

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