Disruption of the growth hormone--signal transducer and activator of transcription 5--insulinlike growth factor 1 axis severely aggravates liver fibrosis in a mouse model of cholestasis.
Disruption of the growth hormone--signal transducer and activator of transcription 5--insulinlike growth factor 1 axis severely aggravates liver fibrosis in a mouse model of cholestasis.
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DOI：
10.1002/hep.23469
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发表时间：
2010-04
期刊：
影响因子：
13.5
通讯作者：
Casanova, Emilio
中科院分区：
文献类型：
--
作者：
Blaas, Leander;Kornfeld, Jan-Wilhelm;Schramek, Daniel;Musteanu, Monica;Zollner, Gernot;Gumhold, Judith;van Zijl, Franziska;Schneller, Doris;Esterbauer, Harald;Egger, Gerda;Mair, Markus;Kenner, Lukas;Mikulits, Wolfgang;Eferl, Robert;Moriggl, Richard;Penninger, Josef;Trauner, Michael;Casanova, Emilio
生长激素（GH）抵抗和低水平的胰岛素样生长因子1（IGF-1）是人类肝纤维化和肝硬化的共同特征。信号转导子和转录激活子5（STAT 5）控制肝脏中的几种重要功能，包括GH介导的IGF-1转录。为了研究STAT 5在肝纤维化中的作用，我们在胆汁淤积的多药耐药基因2敲除（Mdr 2 −/−）小鼠模型中特异性地删除了肝细胞和胆管细胞中的Stat 5a/B位点。双基因敲除小鼠出现早期和严重的肝纤维化表型，伴随着胆汁酸稳态关键调节因子表达的紊乱。Stat 5缺失导致GH抵抗，血清中IGF-1水平检测不到。我们可以观察到重要的肝保护基因，如表皮生长因子受体（Egfr），肝细胞核因子6（Hnf 6），催乳素受体（Prlr）和白血病抑制因子受体（Lifr）的表达减少，以及凋亡肝细胞的数量增加。我们的数据表明，STAT 5的损失使肝细胞对胆汁酸诱导的损伤和细胞凋亡敏感，这些损伤和细胞凋亡是由GH诱导的Igf-1转录的破坏和肝保护基因的下调引起的。这些发现有助于了解肝纤维化和未来的肝纤维化治疗策略。
Growth hormone (GH) resistance and low serum levels of insulinlike growth factor 1 (IGF-1) are common features in human liver fibrosis and cirrhosis. Signal transducer and activator of transcription 5 (STAT5) controls several vital functions in the liver, including GH-mediated transcription of IGF-1. To investigate the role of STAT5 in liver fibrogenesis, we specifically deleted the Stat5a/b locus both in hepatocytes and cholangiocytes in the multidrug resistance gene 2 knockout (Mdr2−/−) mouse model of cholestasis. Double knockout mice develop an early and severe liver fibrosis phenotype, accompanied by perturbed expression of key regulators of bile acid homeostasis. Deletion of Stat5 resulted in GH resistance, and IGF-1 levels in serum were undetectable. We could observe reduced expression of important hepatoprotective genes, such as epidermal growth factor receptor (Egfr), hepatocyte nuclear factor 6 (Hnf6), prolactin receptor (Prlr), and leukemia inhibitory factor receptor (Lifr) as well as increased numbers of apoptotic hepatocytes. Our data suggest that loss of STAT5 sensitizes hepatocytes to bile acid–induced damage and apoptosis caused by disruption of GH-induced transcription of Igf-1 and down-regulation of hepatoprotective genes. These findings could contribute to the understanding of liver fibrosis and future treatment strategies for liver fibrosis.
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影响因子：
2.9
作者：
JAMALL, IS;FINELLI, VN;HEE, SSQ
通讯作者：
HEE, SSQ
DOI：
10.1073/pnas.0409722102
发表时间：
2005-03-01
影响因子：
11.1
作者：
Campbell, JS;Hughes, SD;Fausto, N
通讯作者：
Fausto, N
DOI：
10.1073/pnas.82.24.8681
发表时间：
1985-12-01
影响因子：
11.1
作者：
FRIEDMAN, SL;ROLL, FJ;BISSELL, DM
通讯作者：
BISSELL, DM
影响因子：
25.7
作者：
MOLLER, S;BECKER, U;SKAKKEBAEK, NE
通讯作者：
SKAKKEBAEK, NE
影响因子：
25.7
作者：
Fickert, P;Trauner, M;Denk, H
通讯作者：
Denk, H