Cyclin E1 controls proliferation of hepatic stellate cells and is essential for liver fibrogenesis in mice.
Cyclin E1 controls proliferation of hepatic stellate cells and is essential for liver fibrogenesis in mice.
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Cyclin E1控制肝星状细胞的增殖，对于小鼠的肝纤维发生至关重要。
DOI：
10.1002/hep.25736
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发表时间：
2012-09
期刊：
影响因子：
13.5
通讯作者：
Liedtke, Christian
中科院分区：
文献类型：
--
作者：
Nevzorova, Yulia A.;Bangen, Joerg-Martin;Hu, Wei;Haas, Ute;Weiskirchen, Ralf;Gassler, Nikolaus;Huss, Sebastian;Tacke, Frank;Sicinski, Piotr;Trautwein, Christian;Liedtke, Christian
肝纤维化与静止的肝细胞和肝星状细胞(HSC)进入细胞周期有关。退出静止是由E-型细胞周期蛋白(CcnE1、CcnE2)控制的。因此，本研究的目的是探讨E-型细胞周期蛋白在人和小鼠肝纤维化中的作用。在不同病因的人肝纤维化和肝硬变患者的肝组织和经四氯化碳(CCl4)诱导的小鼠野生型(WT)肝组织中，CcnE1的表达被诱导，而其同系物CcnE2的表达不被诱导。为了进一步评价E-型细胞周期蛋白在肝纤维化形成中的潜在作用，我们用CCl_4重复处理CcnE_1−/−和Cc_nE_2−/−基因敲除小鼠以诱导肝纤维化。有趣的是，ccne1−/−小鼠可以预防CCl_4介导的肝纤维化，表现为I型胶原α_1的表达减少和肝间隔的缺乏。相比之下，CcnE2CCl4治疗后的−/−小鼠表现出加速的纤维化。我们从WT、CcnE_1、Cn_nE_2−/−和Cn_nE_2−/−小鼠体内分离了原代肝星状细胞，并对其体外活化、增殖和存活进行了分析。WT HSC在开始增殖时CcnE1表达最强，转分化为肌成纤维细胞后表达减弱。CcnE1HSC的存活、细胞周期停滞和α-平滑肌肌动蛋白的表达显著降低，提示−/−激活不足。相反，与WT细胞相比，CcnE2缺陷的HSC表达高水平的CcnE1，并表现出更强的细胞周期活性和增殖能力。CcnE1和CcnE2在肝纤维化中具有拮抗作用。CcnE1对HSC的激活、增殖和存活是必不可少的，从而促进细胞外基质的合成和肝纤维化的形成。
Liver fibrogenesis is associated with the transition of quiescent hepatocytes and hepatic stellate cells (HSC) into the cell cycle. Exit from quiescence is controlled by E-type cyclins (CcnE1, CcnE2). Thus, the aim of the current study was to investigate the contribution of E-type cyclins for liver fibrosis in man and mice. Expression of CcnE1, but not of its homologue CcnE2 was induced in fibrotic and cirrhotic livers from human patients with different etiologies and in murine wildtype (WT) livers after periodical administration of the pro-fibrotic toxin carbon tetrachloride (CCl4). To further evaluate the potential function of E-type cyclins for liver fibrogenesis, we repetitively treated constitutive CcnE1−/− and CcnE2−/− knockout mice with CCl4 to induce liver fibrosis. Interestingly, CcnE1−/− mice were protected against CCl4–mediated liver fibrogenesis as evidenced by reduced collagen type I α1 expression and lack of septum formation. In contrast, CcnE2−/− mice showed accelerated fibrogenesis following CCl4 treatment. We isolated primary HSC from WT, CcnE1−/− and CcnE2−/− mice and analyzed their activation, proliferation and survival in vitro. CcnE1 expression in WT HSC was maximal when they started to proliferate, but decreased after the cells transdifferentiated into myofibroblasts. CcnE1−/− HSC showed dramatically impaired survival, cell cycle arrest and strongly reduced expression of alpha-smooth muscle actin, indicating deficient HSC activation. In contrast, CcnE2-deficient HSC expressed elevated level of CcnE1 and showed enhanced cell cycle activity and proliferation compared to WT cells. CcnE1 and CcnE2 have antagonistic roles in liver fibrosis. CcnE1 is indispensable for activation, proliferation and survival of HSC and thus promotes synthesis of extracellular matrix and liver fibrogenesis.
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影响因子：
13.5
作者：
Fausto, N;Campbell, JS;Riehle, KJ
通讯作者：
Riehle, KJ
影响因子：
5
作者：
Borkham-Kamphorst, E;Herrmann, J;Weiskirchen, R
通讯作者：
Weiskirchen, R
影响因子：
5.6
作者：
Sekiya, Yumiko;Ogawa, Tomohiro;Kawada, Norifumi
通讯作者：
Kawada, Norifumi
影响因子：
3.7
作者：
Zimmermann HW;Seidler S;Nattermann J;Gassler N;Hellerbrand C;Zernecke A;Tischendorf JJ;Luedde T;Weiskirchen R;Trautwein C;Tacke F
通讯作者：
Tacke F
影响因子：
64.5
作者：
Geng, Y;Yu, QY;Sicinski, P
通讯作者：
Sicinski, P