Hepatic deletion of Smad7 in mouse leads to spontaneous liver dysfunction and aggravates alcoholic liver injury.
Hepatic deletion of Smad7 in mouse leads to spontaneous liver dysfunction and aggravates alcoholic liver injury.
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小鼠肝脏中 Smad7 缺失导致自发性肝功能障碍并加重酒精性肝损伤
DOI：
10.1371/journal.pone.0017415
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发表时间：
2011-02-28
期刊：
影响因子：
3.7
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Zhu L;Wang L;Wang X;Luo X;Yang L;Zhang R;Yin H;Xie D;Pan Y;Chen Y
TGF-β 已知在多种肝脏疾病中发挥重要作用，包括纤维化和酒精性脂肪肝。 Smad7 是 TGF-β 信号传导的细胞内负调节因子。目前尚不清楚内源性Smad7是否对肝功能和酒精性肝损伤有影响。我们使用 Cre/loxP 系统，将 Alb-Cre 小鼠与 Smad7loxP/loxP 小鼠杂交，产生 Smad7 的肝脏特异性缺失，同时丢失了不可或缺的 MH2 结构域。通过给小鼠喂食含有 5% 乙醇的流质饮食 6 周，然后灌胃单剂量乙醇，从而实现酒精性肝损伤。肝脏中 Smad7 的缺失与肝脏中 Smad2/3 磷酸化的增加或原代肝细胞中 TGF-β 处理后的增加有关。大多数肝脏特异性缺失 Smad7 (Smad7liver-KO) 的小鼠均能存活且表型正常，肝脏中 Smad7 表达仅轻微或没有减少。然而，约30%的Smad7高效缺失的Smad7liver-KO小鼠出现自发性肝功能障碍，表现为体重低、整体恶化、血清AST和ALT水平升高。在这些小鼠中观察到肝细胞变性和凋亡增加。在 Smad7 缺失的原代肝细胞中，TGF-β 诱导的上皮间质转化 (EMT) 加速。此外，在 Smad7 缺陷小鼠中，酒精引起的肝损伤和脂肪变性严重加剧，这与参与脂肪生成和炎症的关键基因的上调有关。此外，肝细胞中 Smad7 缺失显着消除了酒精诱导的 ADH1 表达。在这项研究中，我们提供的体内证据表明内源性 Smad7 在肝功能和酒精性肝损伤中发挥着重要作用。
TGF-β has been known to play an important role in various liver diseases including fibrosis and alcohol-induced fatty liver. Smad7 is an intracellular negative regulator of TGF-β signaling. It is currently unclear whether endogenous Smad7 has an effect on liver function and alcoholic liver damage. We used Cre/loxP system by crossing Alb-Cre mice with Smad7loxP/loxP mice to generate liver-specific deletion of Smad7 with loss of the indispensable MH2 domain. Alcoholic liver injury was achieved by feeding mice with a liquid diet containing 5% ethanol for 6 weeks, followed by a single dose of ethanol gavage. Deletion of Smad7 in the liver was associated with increased Smad2/3 phosphorylation in the liver or upon TGF-β treatment in primary hepatocytes. The majority of mice with liver specific deletion of Smad7 (Smad7liver-KO) were viable and phenotypically normal, accompanied by only slight or no reduction of Smad7 expression in the liver. However, about 30% of Smad7liver-KO mice with high efficiency of Smad7 deletion had spontaneous liver dysfunction, demonstrated as low body weight, overall deterioration, and increased serum levels of AST and ALT. Degeneration and elevated apoptosis of liver cells were observed with these mice. TGF-β-induced epithelial to mesenchymal transition (EMT) was accelerated in Smad7-deleted primary hepatocytes. In addition, alcohol-induced liver injury and steatosis were profoundly aggravated in Smad7 deficient mice, associated with upregulation of critical genes involved in lipogenesis and inflammation. Furthermore, alcohol-induced ADH1 expression was significantly abrogated by Smad7 deletion in hepatocytes. In this study, we provided in vivo evidence revealing that endogenous Smad7 plays an important role in liver function and alcohol-induced liver injury.
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DOI：
10.1073/pnas.93.12.5877
发表时间：
1996-06-11
影响因子：
11.1
作者：
Bottinger, EP;Factor, VM;Sporn, MB
通讯作者：
Sporn, MB
影响因子：
29.4
作者：
Dooley, Steven;Hamzavi, Jafar;Mertens, Peter R.
通讯作者：
Mertens, Peter R.
影响因子：
4.4
作者：
Li, Ronggui;Rosendahl, Alexander;Heuchel, Rainer L.
通讯作者：
Heuchel, Rainer L.
影响因子：
3.5
作者：
Huang, Zheng;Wang, Degang;Martin, James F.
通讯作者：
Martin, James F.
影响因子：
13.5
作者：
Taura, Kojiro;Miura, Kouichi;Iwaisako, Keiko;Osterreicher, Christoph H.;Kodama, Yuzo;Penz-Osterreicher, Melitta;Brenner, David A.
通讯作者：
Brenner, David A.