Disruption of Estrogen Receptor Alpha in Rats Results in Faster Initiation of Compensatory Regeneration Despite Higher Liver Injury After Carbon Tetrachloride Treatment.
Disruption of Estrogen Receptor Alpha in Rats Results in Faster Initiation of Compensatory Regeneration Despite Higher Liver Injury After Carbon Tetrachloride Treatment.
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DOI：
10.1177/1091581817706067
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发表时间：
2017
影响因子：
2.2
通讯作者：
Apte U
中科院分区：
文献类型：
--
作者：
McGreal SR;Rumi K;Soares MJ;Woolbright BL;Jaeschke H;Apte U
雌激素受体α（ESR1）是雌激素的两种细胞内受体之一，由肝脏中的肝细胞表达。 ESR1 在调节毒物引起的肝损伤和代偿性再生中的作用尚不完全清楚。我们使用野生型（WT）和ESR1敲除大鼠（ESR1-KO）研究了ESR1在四氯化碳（CCl4）诱导的肝损伤后肝再生中的作用。成年雌性 WT 和 ESR1-KO 大鼠用 1ml/kg CCl4 处理，并在 0-48 小时的时间内安乐死。通过血清丙氨酸氨基转氨酶 (ALT) 测量的肝损伤和组织病理学分析显示，与 WT 大鼠相比，ESR1-KO 大鼠的肝损伤明显更高。苏木精和伊红 (H&E) 染色显示 ESR1-KO 大鼠的坏死率高出两倍，并且有明显的炎症细胞浸润。氯乙酸酯酶染色显示 ESR1-KO 大鼠肝脏中中性粒细胞浸润较高。有趣的是，增殖细胞核抗原（PCNA）免疫组织化学显示，尽管 ESR1KO 大鼠的肝损伤高出两倍，但与 WT 大鼠相比，ESR1KO 大鼠的肝再生能力相同。蛋白质印迹分析显示，细胞周期蛋白 D1 和磷酸化 Rb（参与细胞周期启动的蛋白质）在 ESR1KO 大鼠的所有时间点均显着升高。进一步的分析显示，在 CCl4 处理后 12 小时，ESR1-KO 大鼠中经典 Wnt/β-catenin 和 NF-κB 信号的激活更快，其特征是更高的激活 β-catenin 和磷酸化 p65。总而言之，这些数据表明，ESR1 介导的信号传导通过下调 Wnt 信号传导来抑制肝脏再生，从而导致化学诱导的肝损伤后细胞周期蛋白 D1 的激活降低。
Estrogen receptor alpha (ESR1) is one of the two intracellular receptors for estrogen and is expressed by hepatocytes in the liver. The role of ESR1 in the regulation of toxicant-induced liver injury and compensatory regeneration is not completely clear. We investigated the role of ESR1 in liver regeneration after carbon tetrachloride (CCl4)-induced liver injury using wild type (WT) and ESR1 knockout rats (ESR1-KO). Adult female WT and ESR1-KO rats were treated with 1ml/kg CCl4 and euthanized over a time course of 0–48 hr. Liver Injury measured by serum alanine amino transaminase (ALT) and histopathological analysis showed significantly higher liver injury in ESR1-KO as compared to WT rats. Hematoxylin and eosin (H&E) staining revealed two-fold higher necrosis and significant inflammatory cell infiltration in ESR1-KO rats. Chloracetate esterase staining revealed higher neutrophil infiltration in ESR1-KO rat livers. Interestingly, Proliferating cell nuclear antigen (PCNA) immunohistochemistry showed that in spite of two-fold higher liver injury, the ESR1KO rats had equal liver regeneration as compared to WT rats. Western blot analysis of cyclin D1 and phosphorylated Rb, proteins involved in the initiation of the cell cycle, were significantly higher at all time points in ESR1KO rats. Further analysis revealed faster activation of canonical Wnt/β-catenin and NF-κB signaling in ESR1-KO rats characterized by higher activated β-catenin and phosphorylated p65 at 12 hr after CCl4 treatment. Taken together, these data indicate that ESR1-mediated signaling inhibits liver regeneration by down regulation of Wnt signaling resulting in lower cyclin D1 activation after chemical-induced liver injury.
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影响因子：
6
作者：
Apte, Udayan;Singh, Sucha;Monga, Satdarshan P. S.
通讯作者：
Monga, Satdarshan P. S.
影响因子：
13.5
作者：
Borude, Prachi;Edwards, Genea;Walesky, Chad;Li, Feng;Ma, Xiaochao;Kong, Bo;Guo, Grace L.;Apte, Udayan
通讯作者：
Apte, Udayan
DOI：
10.1152/ajpgi.00359.2006
发表时间：
2007-06-01
影响因子：
4.5
作者：
Apte, Udayan;Zeng, Gang;Monga, Satdarshan P. S.
通讯作者：
Monga, Satdarshan P. S.
DOI：
10.1073/pnas.1315319110
发表时间：
2013-10-29
影响因子：
11.1
作者：
Hong, Eui-Ju;Levasseur, Marie-Pier;Giguere, Vincent
通讯作者：
Giguere, Vincent
影响因子：
3.1
作者：
Barone, M;Ladisa, R;Iolascon, A
通讯作者：
Iolascon, A