Lack of Interleukin-6/Glycoprotein 130/Signal Transducers and Activators of Transcription-3 Signaling in Hepatocytes Predisposes to Liver Steatosis and Injury in Mice
Lack of Interleukin-6/Glycoprotein 130/Signal Transducers and Activators of Transcription-3 Signaling in Hepatocytes Predisposes to Liver Steatosis and Injury in Mice
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DOI：
10.1002/hep.23322
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发表时间：
2010-02-01
期刊：
影响因子：
13.5
通讯作者：
Streetz, Konrad L.
中科院分区：
文献类型：
--
作者：
Kroy, Daniela C.;Beraza, Naiara;Streetz, Konrad L.
细胞因子平衡失调参与触发从脂肪变性到非酒精性脂肪性肝炎的进程，最终导致肝纤维化和癌症。为了更好地确定促炎性白细胞介素 - 6（IL - 6）型细胞因子在肝细胞中的作用，我们在脂肪性肝炎小鼠模型中研究了IL - 6及其共享受体糖蛋白130（gp130）的作用。给IL - 6（-/-）小鼠喂食缺乏胆碱、添加乙硫氨酸（CDE）的饮食。使用条件性gp130基因敲除和敲入小鼠来实现肝细胞特异性的gp130缺失（gp130（Δhepa））、gp130依赖性大鼠肉瘤（Ras） - （gp130（ΔhepaRas））以及信号转导和转录激活因子（STAT） - （gp130（ΔhepaSTAT））激活。经CDE处理的IL - 6（-/-）小鼠在喂食2周后显示出明显的肝脏脂肪变性。这些小鼠迅速出现空腹血糖、胰岛素血清水平和转氨酶升高。为了更好地确定依赖于IL - 6的细胞内通路，特别是在肝细胞中，我们接下来给gp130（Δhepa）小鼠喂食CDE饮食。这些动物也出现明显的脂肪变性伴高血糖，并显示胰岛素血清水平升高。此外，gp130（Δhepa）动物表现出炎症反应失衡，肝脏肿瘤坏死因子 - α增加，脂联素信使RNA水平降低。对肝细胞特异性gp130依赖性通路的剖析显示，gp130（ΔhepaSTAT）小鼠有类似的疾病表型，而gp130（ΔhepaRas）动物受到保护。在经CDE处理的小鼠中，gp130 - STAT3信号缺失与免疫细胞浸润、JUN激酶激活、急性期反应减弱以及转氨酶升高有关。此外，与gp130（ΔhepaRas）小鼠和对照组相比，gp130（Δhepa）和gp130（ΔhepaSTAT）小鼠显示出肝纤维化的初始迹象。结论：在CDE处理期间，肝细胞中缺乏IL - 6和gp130 - STAT信号的小鼠容易出现肝脏代谢变化和炎症。这最终导致进行性脂肪性肝炎，并伴有肝脏重塑的迹象。因此，所提出的模型使人们能够进一步剖析在脂肪肝变性过程中肝细胞中IL - 6 / gp130型信号的作用，以确定代谢性肝病的新治疗靶点。（《肝脏病学》2010年；51：463 - 473）
A deregulated cytokine balance is involved in triggering the sequence from steatosis to nonalcoholic steatohepatitis, ultimately leading to liver fibrosis and cancer. To better define the role of proinflammatory interleukin-6 (IL-6)-type cytokines in hepatocytes we investigated the role of IL-6 and its shared receptor, glycoprotein 130 (gp130), in a mouse model of steatohepatitis. IL-6(-/-) mice were fed a choline-deficient, ethionine-supplemented (CDE) diet. Conditional gp130 knockout and knockin mice were used to achieve hepatocyte-specific deletion of gp130 (gp130(Delta hepa)), gp130-dependent rat sarcoma (Ras)-(gp130(Delta hepaRas)) and signal transducers and activators of transcription (STAT)-(gp130(Delta hepaSTAT)) activation. CDE-treated IL-6(-/-) mice showed a significant hepatic steatosis at 2 weeks after feeding. The mice rapidly developed elevated fasting blood glucose, insulin serum levels, and transaminases. To better define IL-6-dependent intracellular pathways, specifically in hepatocytes, we next treated gp130(Delta hepa) mice with a CDE diet. These animals also developed a marked steatosis with hyperglycemia and displayed elevated insulin serum levels. Additionally, gp130(Delta hepa) animals showed an imbalanced inflammatory response with increased hepatic tumor necrosis factor-alpha and decreased adiponectin messenger RNA levels. Dissecting the hepatocyte-specific gp130-dependent pathways revealed a similar disease phenotype in gp130(Delta hepaSTAT) mice, whereas gp130(Delta hepaRas) animals were protected. In CDE-treated mice lack of gp130-STAT3 signaling was associated with immune-cell-infiltration, jun kinase-activation, a blunted acute-phase-response, and elevated transaminases. Further-more, gp130(Delta hepa) and gp130(Delta hepaSTAT) mice showed beginning signs of liver fibrosis compared to gp130(Delta hepaRas) mice and controls. Conclusion: During CDE treatment mice lacking IL-6 and gp130-STAT signaling in hepatocytes are prone to hepatic metabolic changes and inflammation. This ultimately leads to progressive steatohepatitis with signs of liver remodeling. Thus, the presented model allows one to further dissect the role of IL-6/gp130-type signaling in hepatocytes during fatty liver degeneration to define new therapeutic targets in metabolic liver diseases. (HEPATOLOGY 2010;51:463-473.)