Hepatocyte estrogen sulfotransferase inhibition protects female mice from concanavalin A-induced T cell-mediated hepatitis independent of estrogens.
Hepatocyte estrogen sulfotransferase inhibition protects female mice from concanavalin A-induced T cell-mediated hepatitis independent of estrogens.
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DOI：
10.1016/j.jbc.2023.103026
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发表时间：
2023-03
影响因子：
4.8
通讯作者：
Xie, Wen
中科院分区：
文献类型：
--
作者：
Wang, Jingyuan;Zhang, Ziteng;Guan, Jibin;Tung, Hung-Chun;Xie, Jiaxuan;Huang, Haozhe;Chen, Yuang;Xu, Meishu;Ren, Songrong;Li, Song;Zhang, Min;Yang, Da;Xie, Wen
自身免疫性肝炎（AIH）是一种典型的T细胞介导的慢性肝病，女性发病率较高。然而，女性易感性的分子机制知之甚少。雌激素磺基转移酶（Est）是一种结合酶，以其磺化和灭活雌激素的功能而闻名。本研究的目的是调查Est是否以及如何在女性AIH的高发病率中发挥作用。用刀豆球蛋白A（ConA）诱导雌性小鼠T细胞介导的肝炎。我们首先表明，Est是高度诱导的刀豆蛋白A处理的小鼠的肝脏。全身或肝细胞特异性消融Est，或药理学抑制Est，保护雌性小鼠免受ConA诱导的肝炎，无论卵巢切除术，表明Est抑制的效果是雌激素无关的。与此相反，我们发现，肝细胞特异性转基因重建Est在全身Est敲除（EstKO）小鼠废除了保护性表型。在ConA攻击后，EstKO小鼠表现出更强烈的炎症反应，促炎细胞因子的产生增加，免疫细胞的肝脏浸润改变。从机制上讲，我们确定Est的消融导致脂质运载蛋白2（Lcn2）的肝脏诱导，而Lcn2的消融消除了EstKO雌性动物的保护性表型。我们的研究结果表明，肝细胞Est所需的雌性小鼠的敏感性ConA诱导和T细胞介导的肝炎在雌激素非依赖性的方式。Est消融可能通过上调Lcn2保护雌性小鼠免受ConA诱导的肝炎。药物抑制Est可能是治疗AIH的潜在策略。
Autoimmune hepatitis (AIH) is a typical T cell–mediated chronic liver disease with a higher incidence in females. However, the molecular mechanism for the female predisposition is poorly understood. Estrogen sulfotransferase (Est) is a conjugating enzyme best known for its function in sulfonating and deactivating estrogens. The goal of this study is to investigate whether and how Est plays a role in the higher incidence of AIH in females. Concanavalin A (ConA) was used to induce T cell–mediated hepatitis in female mice. We first showed that Est was highly induced in the liver of ConA-treated mice. Systemic or hepatocyte-specific ablation of Est, or pharmacological inhibition of Est, protected female mice from ConA-induced hepatitis regardless of ovariectomy, suggesting the effect of Est inhibition was estrogen independent. In contrast, we found that hepatocyte-specific transgenic reconstitution of Est in the whole-body Est knockout (EstKO) mice abolished the protective phenotype. Upon the ConA challenge, EstKO mice exhibited a more robust inflammatory response with elevated production of proinflammatory cytokines and changed liver infiltration of immune cells. Mechanistically, we determined that ablation of Est led to the hepatic induction of lipocalin 2 (Lcn2), whereas ablation of Lcn2 abolished the protective phenotype of EstKO females. Our findings demonstrate that hepatocyte Est is required for the sensitivity of female mice to ConA-induced and T cell–mediated hepatitis in an estrogen-independent manner. Est ablation may have protected female mice from ConA-induced hepatitis by upregulating Lcn2. Pharmacological inhibition of Est might be a potential strategy for the treatment of AIH.
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影响因子：
7.7
作者：
Gao J;He J;Shi X;Stefanovic-Racic M;Xu M;O'Doherty RM;Garcia-Ocana A;Xie W
通讯作者：
Xie W
DOI：
10.1016/j.bbadis.2013.01.014
发表时间：
2013-05-01
影响因子：
6.2
作者：
Borkham-Kamphorst, Erawan;de Leur, Eddy van;Weiskirchen, Ralf
通讯作者：
Weiskirchen, Ralf
影响因子：
5.1
作者：
Gao L;Li B;Wang J;Shen D;Yang M;Sun R;Tung HC;Xu M;Ren S;Zhang M;Yang D;Lu B;Wang H;Liu Y;Xie W
通讯作者：
Xie W
雌激素磺基转移酶是一种氧化应激反应基因，对肝脏缺血/再灌注损伤具有性别特异性影响。
影响因子：
4.8
作者：
Guo, Yan;Hu, Bingfang;Xie, Wen
通讯作者：
Xie, Wen
影响因子：
2.4
作者：
Heymann, F.;Hamesch, K.;Tacke, F.
通讯作者：
Tacke, F.