Evolution of hepatic steatosis to fibrosis and adenoma formation in liver-specific growth hormone receptor knockout mice.
Evolution of hepatic steatosis to fibrosis and adenoma formation in liver-specific growth hormone receptor knockout mice.
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DOI：
10.3389/fendo.2014.00218
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发表时间：
2014
影响因子：
5.2
通讯作者：
Sperling MA
中科院分区：
文献类型：
--
作者：
Fan Y;Fang X;Tajima A;Geng X;Ranganathan S;Dong H;Trucco M;Sperling MA
背景资料：非酒精性脂肪性肝病（NAFLD）是与肥胖和胰岛素抵抗密切相关的慢性肝病的最常见形式之一;肝脏中生长激素（GH）作用不足被认为是一种机制。在这里，我们研究了肝脏特异性GHR缺失的老年小鼠中NAFLD的演变。方法：我们检测了老年雄性小鼠（44-50周）GHRLD的糖耐量，胰岛素反应性和血脂谱。我们进行了蛋白质组学分析，基于路径的Superarray分析，以及定量RT-PCR，以获得对GHR缺乏介导的NAFLD的分子机制的深入了解。此外，我们还观察了老年GHRLD雄性小鼠肝脏的病理变化。结果如下：生化特征与代谢综合征一致：糖耐量异常、胰岛素分泌受损和高脂血症。炎症关键标志物的RT-qPCR分析显示TNFα和CCL 3增加3 - 5倍，证实存在炎症。纤维化标志物（例如，Col 1A 2和Col 3A 1）显著增加，同时TGFβ转录物增加2 - 3倍。蛋白质组学分析显示Mup 1和Selenbp 2显著减少。此外，通路分析表明，细胞周期和生长相关基因（即，Ccnd 1、Socs 2、Socs 3和Egfr）在GHRLD肝脏中受到显著影响。GHRLD肝脏的显微镜分析（H&E）显示存在不同恶性阶段的肝腺瘤。结论：男性肝脏中GH信号传导的消除导致代谢综合征、肝脂肪变性、炎症和纤维化增加以及肝肿瘤的发展。由于肥胖是NAFLD的常见前体，是GH分泌和作用不足的状态，因此GHRLD模型可用于揭示受损的肝脏GH信号传导在这些病理过程中的作用，并有助于确定潜在的干预靶点。
Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver diseases closely associated with obesity and insulin resistance; deficient growth hormone (GH) action in liver has been implicated as a mechanism. Here, we investigated the evolution of NAFLD in aged mice with liver-specific GHR deletion. Methods: We examined glucose tolerance, insulin responsiveness, and lipid profiles in aged male mice (44–50 weeks) with GHRLD. We performed proteomics analysis, pathway-based Superarray assay, as well as quantitative RT-PCR to gain molecular insight into the mechanism(s) of GHR-deficiency-mediated NAFLD. In addition, we examined the pathological changes of livers of aged GHRLD male mice. Results: The biochemical profile was consistent with that of the metabolic syndrome: abnormal glucose tolerance, impaired insulin secretion, and hyperlipidemia. RT-qPCR analysis of key markers of inflammation revealed a three- to fivefold increase in TNFα and CCL3, confirming the presence of inflammation. Expression of fibrotic markers (e.g., Col1A2 and Col3A1) was significantly increased, together with a two- to threefold increase in TGFβ transcripts. Proteomics analyses showed a marked decrease of Mup1 and Selenbp2. In addition, pathway-analysis showed that the expression of cell cycle and growth relevant genes (i.e., Ccnd1, Socs2, Socs3, and Egfr) were markedly affected in GHRLD liver. Microscopic analyses (H&E) of GHRLD livers revealed the presence of hepatic adenomas of different stages of malignancy. Conclusion: Abrogation of GH signaling in male liver leads to metabolic syndrome, hepatic steatosis, increased inflammation and fibrosis, and development of hepatic tumor. Since obesity, a common precursor of NAFLD, is a state of deficient GH secretion and action, the GHRLD model could be used to unravel the contribution of compromised hepatic GH signaling in these pathological processes, and help to identify potential targets for intervention.
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影响因子：
5.2
作者：
Malaguarnera R;Belfiore A
通讯作者：
Belfiore A
影响因子：
13.5
作者：
Birkenfeld, Andreas L.;Shulman, Gerald I.
通讯作者：
Shulman, Gerald I.
影响因子：
5.1
作者：
Goodman, Zachary D.
通讯作者：
Goodman, Zachary D.
影响因子：
2.4
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Giorgio V;Prono F;Graziano F;Nobili V
通讯作者：
Nobili V
影响因子：
13.5
作者：
Friedbichler, Katrin;Themanns, Madeleine;Moriggl, Richard
通讯作者：
Moriggl, Richard