Inflammation-associated interleukin-6/signal transducer and activator of transcription 3 activation ameliorates alcoholic and nonalcoholic fatty liver diseases in interleukin-10-deficient mice.
Inflammation-associated interleukin-6/signal transducer and activator of transcription 3 activation ameliorates alcoholic and nonalcoholic fatty liver diseases in interleukin-10-deficient mice.
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DOI：
10.1002/hep.24517
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发表时间：
2011-09-02
期刊：
影响因子：
--
通讯作者：
Gao B
中科院分区：
文献类型：
--
作者：
Miller AM;Wang H;Bertola A;Park O;Horiguchi N;Ki SH;Yin S;Lafdil F;Gao B
酒精性和非酒精性脂肪性肝炎的特征是脂肪肝伴有炎症。人们普遍认为脂肪变性会促进炎症，而炎症反过来又会加重脂肪变性。因此，我们假设白细胞介素 - 10（IL - 10）这种关键的抗炎细胞因子的缺失会加剧酒精性和非酒精性脂肪性肝病模型中的肝脏炎症、脂肪变性和肝细胞损伤。这两种模型分别是通过给小鼠喂食含5%乙醇的液体饲料4周或高脂肪饲料12周构建的。我们培育并使用了IL - 10基因敲除（IL - 10−/−）小鼠和其他几种转基因小鼠品系。与野生型小鼠相比，IL - 10−/−小鼠在酒精或高脂肪饮食喂养后肝脏炎症反应更强，白细胞介素 - 6水平更高，肝脏信号转导和转录激活因子3（STAT3）的激活程度更高，但脂肪变性和肝细胞损伤较轻。额外敲除IL - 6或肝脏STAT3可恢复脂肪变性和肝细胞损伤，但会进一步增强IL - 10−/−小鼠的肝脏炎症反应。此外，IL - 10−/−小鼠肝脏中固醇调节元件结合蛋白1c（SREBP1c）以及脂肪酸合成中关键的下游脂肪生成蛋白和酶的表达下调。相反，IL - 10−/−小鼠肝脏中磷酸化腺苷酸活化蛋白激酶（AMPK）及其下游靶点包括磷酸化的乙酰辅酶A羧化酶1（ACC1）和肉碱/有机阳离子转运体2（CPT - 1）的水平升高。这些失调在IL - 10−/−IL - 6−/−或IL - 10−/−STAT3Hep−/−双基因敲除小鼠中得到纠正。总之，IL - 10−/−小鼠易发生肝脏炎症反应，但对乙醇或高脂肪饮食诱导的脂肪变性和肝细胞损伤具有抵抗力。这些小鼠对脂肪变性的抵抗力可归因于炎症相关的肝脏IL - 6/STAT3激活升高，这随后下调了肝脏中的脂肪生成基因，但上调了脂肪酸氧化相关基因。
Alcoholic and nonalcoholic steatohepatitis are characterized by fatty liver plus inflammation. It is generally believed that steatosis promotes inflammation, while inflammation in turn aggregates steatosis. Thus, we hypothesized the deletion of interleukin-10 (IL-10), a key anti-inflammatory cytokine, exacerbates liver inflammation, steatosis, and hepatocellular damage in alcoholic and nonalcoholic fatty liver disease models that were achieved via feeding mice with a liquid diet containing 5% ethanol for 4 weeks or a high fat diet for 12 weeks, respectively. IL-10 knockout (IL-10−/−) mice and several other strains of genetically modified mice were generated and used. Compared to wild-type mice, IL-10−/− mice had greater liver inflammatory response with higher levels of IL-6 and hepatic signal transducer and activator of transcription 3 (STAT3) activation, but less steatosis and hepatocellular damage after alcohol or high fat diet feeding. An additional deletion of IL-6 or hepatic STAT3 restored steatosis and hepatocellular damage but further enhanced liver inflammatory response in IL-10−/− mice. In addition, the hepatic expression of SREBP1c and key downstream lipogenic proteins and enzymes in fatty acid synthesis were downregulated in IL-10−/− mice. Conversely, IL-10−/− mice displayed enhanced levels of phosphorylated AMPK and its downstream targets including phosphorylated ACC1 and CPT-1 in the liver. Such dysregulations were corrected in IL-10−/−IL-6−/− or IL-10−/−STAT3Hep−/− double knockout mice. In conclusion, IL-10−/− mice are prone to liver inflammatory response but resistant to steatosis and hepatocellular damage induced by ethanol or high fat diet feeding. Resistance to steatosis in these mice is attributable to elevation of inflammation-associated hepatic IL-6/STAT3 activation that subsequently downregulates lipogenic genes but upregulates fatty acid oxidation-associated genes in the liver.
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影响因子：
29.4
作者：
Miura K;Kodama Y;Inokuchi S;Schnabl B;Aoyama T;Ohnishi H;Olefsky JM;Brenner DA;Seki E
通讯作者：
Seki E
影响因子：
4.8
作者：
den Boer, Marion A. M.;Voshol, Peter J.;Romijn, Johannes A.
通讯作者：
Romijn, Johannes A.
影响因子：
13.5
作者：
Kroy, Daniela C.;Beraza, Naiara;Streetz, Konrad L.
通讯作者：
Streetz, Konrad L.
影响因子：
13.5
作者：
Feldstein, AE;Werneburg, NW;Gores, GJ
通讯作者：
Gores, GJ
影响因子：
13.5
作者：
Douglas, Diana B.;Beiting, Daniel P.;Loftus, John P.;Appleton, Judith A.;Bliss, Susan K.
通讯作者：
Bliss, Susan K.