UDCA and CDCA alleviate 17α-ethinylestradiol-induced cholestasis through PKA-AMPK pathways in rats
UDCA and CDCA alleviate 17α-ethinylestradiol-induced cholestasis through PKA-AMPK pathways in rats
复制标题
UDCA和CDCA通过PKA-AMPK途径减轻大鼠17α-炔雌醇诱导的胆汁淤积
DOI：
10.1016/j.taap.2016.10.011
复制
发表时间：
2016-11-15
影响因子：
3.8
通讯作者：
Jiang, Zhenzhou
中科院分区：
文献类型：
--
作者：
Li, Xiaojiaoyang;Yuan, Zihang;Jiang, Zhenzhou
雌激素诱导的妊娠期胆汁淤积症，又称妊娠期肝内胆汁淤积症，是一种被广泛认为是女性或妊娠特有的雌激素相关性肝病。我们以前的研究结果表明，合成雌激素17α-乙炔雌二醇(EE)通过ERK1/2-LKB1-AMP激活的蛋白激酶(AMPK)信号通路及其对法尼醇X受体(FXR)的抑制而诱导胆汁淤积性损伤。为了探讨胆汁酸在EE诱导的胆汁淤积中的作用，我们观察了鹅去氧胆酸(CDCA)、熊去氧胆酸(UDCA)和脱氧胆酸(DCA)对夹心培养大鼠原代肝细胞(SCRHs)和在体大鼠模型的影响。结果表明，CDCA和UDCA均能显著降低SCRH细胞AMPK的磷酸化水平，且呈时间和浓度依赖性。尽管CDCA和UDCA对FXR的激活有不同的影响，但CDCA和UDCA均可抑制EE诱导的AMPK激活，同时上调FXR及其下游胆汁酸转运体的表达。然而，DCA虽然激活FXR并诱导SHP，但不能减轻EE诱导的FXR抑制，进一步加重EE诱导的胆汁淤积。我们进一步证明，CDCA和UDCA，而不是DCA，都能激活SCRH和8周龄雄性大鼠肝脏中的cAMP依赖蛋白激酶(PICA)。此外，PICA拮抗剂H89可阻断CDCA和UDCA对AMPK的抑制作用，PICA的药理和遗传激活可抑制EE诱导的AMPK激活及其下游效应。综上所述，这些结果提示CDCA和UDCA通过PKA信号通路和上调EE抑制的FXR对雌激素诱导的胆汁淤积损伤具有保护作用，这可能是治疗ICP的潜在靶点。(C)2016 Elsevier Inc.保留所有权利。
Estrogen-induced cholestasis, known as intrahepatic cholestasis of pregnancy (ICP), is an estrogen-related liver disease that is widely recognized as female or pregnancy-specific. Our previous findings showed that the synthetic estrogen, 17 alpha-ethinylestradiol (EE), induced cholestatic injury through ERK1/2-LKB1-AMP-activated protein kinase (AMPK) signaling pathway and its mediated suppression of farnesoid X receptor (FXR). To investigate the role played by bile acids in EE-induced cholestasis, we evaluated the effects of chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA) on sandwich cultured rat primary hepatocytes (SCRHs) and an in vivo rat model. Our results showed that, both CDCA and UDCA significantly induced time- and concentration-dependent reduction in AMPK phosphorylation in SCRHs. Despite having different effects on FXR activation, CDCA and UDCA both inhibited EE-induced AMPK activation, accompanied with the up-regulation of FXR and its downstream bile acid transporters. However, although DCA activates FXR and induces SHP, it was unable to alleviate EE-induced FXR suppression and further aggravated EE-induced cholestasis. We further demonstrated that both CDCA and UDCA, but not DCA, activated cyclic AMP dependent protein kinase (PICA) in SCRHs and the livers of male rats (8 weeks old) liver. Furthermore, PICA antagonist, H89, blocked the AMPK inhibition by CDCA and UDCA, and pharmacological and genetic activation of PICA suppressed EE-induced AMPK activation and its downstream effects. Collectively, these results suggest that CDCA and UDCA protect against estrogen-induced cholestatic injury via PKA signaling pathway and up-regulation of EE-suppressed FXR, which suggests a potential therapeutic target for ICP. (C) 2016 Elsevier Inc. All rights reserved.