Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice
Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice
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DOI：
10.1136/gutjnl-2011-300269
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发表时间：
2012-07-01
期刊：
影响因子：
24.5
通讯作者：
Xu, Aimin
中科院分区：
文献类型：
--
作者：
Ye, Dewei;Li, Francois Y. L.;Xu, Aimin
背景非酒精性脂肪性肝病(NASH)是一种与肥胖相关的慢性肝病，范围从单纯性脂肪变性到非酒精性脂肪性肝炎(NASH)，可发展为肝纤维化和肝硬变。目的探讨Toll样受体(TLR4)4在脂肪变性向炎症转化过程中的作用。方法将ApoE(-/-)/TLR4野生型小鼠(ApoE(-/-)/TLR4-WT)与TLR4突变(TLR4突变)小鼠杂交，建立ApoE(-/-)/TLR4-WT小鼠结果高胆固醇饮食喂养12周后，ApoE(-/-)/TLR4-WT小鼠出现典型的NASH病理特征，与肥胖和代谢综合征相关。相比之下，缺乏功能性TLR4的ApoE(-/-)/TLR4mut小鼠对HFHC饮食诱导的肝脏炎症和损伤具有抵抗力，对饮食诱导的活性氧物种(ROS)和促炎细胞因子的产生较不敏感。在ApoE(-/-)/TLR4-WT小鼠中，参与未折叠蛋白反应的转录因子X-box结合蛋白-1(XBP-1)在肝脏中被HFHC饮食激活，而在ApoE(-/-)/TLR4mut小鼠中XBP-1的激活被取消。在原代培养的大鼠Kupffer细胞中，内毒素通过产生ROS诱导XBP-1激活，而siRNA介导的XBP-1表达下调导致内毒素诱导的NF-kappa B激活和细胞因子产生显著减少。此外，腺病毒介导的显性负性XBP-1的表达显著减轻了HFHC饮食诱导的小鼠肝脏炎症和损伤。结论这些发现支持Kupffer细胞中的TLR4通过诱导ROS依赖的XBP-1激活，在介导单纯性脂肪变性向NASH的进展中发挥关键作用。
Background Non-alcoholic fatty liver disease is an obesity-related chronic liver disorder ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis.Objective Tto investigate the role of Toll-like receptor (TLR) 4 in mediating the transition from steatosis to inflammation.Methods ApoE(-/-)/TLR4mut mice and ApoE(-/-)/TLR4 wild-type mice (ApoE(-/-)/TLR4-WT) were generated by cross-breeding an ApoE-deficient (ApoE(-/-)) strain with TLR4-mutant (TLR4mut) mice, which were fed with high-fat, high-cholesterol (HFHC) diet to induce obesity.Results ApoE(-/-)/TLR4-WT mice fed with an HFHC diet for 12 weeks developed typical pathological features of NASH, which is associated with obesity and the metabolic syndrome. By contrast, ApoE(-/-)/TLR4mut mice lacking functional TLR4 were resistant to HFHC diet-induced liver inflammation and injury and were less susceptible to the diet-induced production of reactive oxygen species (ROS) and proinflammatory cytokines. In ApoE(-/-)/TLR4-WT mice, X-box binding protein-1 (XBP-1), a transcription factor involved in the unfolded protein responses, was activated in the liver by an HFHC diet, whereas XBP-1 activation was abrogated in ApoE(-/-)/TLR4mut mice. In primary rat Kupffer cells, endotoxin induced XBP-1 activation through ROS production, whereas siRNA-mediated knockdown of XBP-1 expression resulted in a marked attenuation in endotoxin-evoked NF-kappa B activation and cytokine production. Furthermore, adenovirus-mediated expression of dominant negative XBP-1 led to a significant attenuation in HFHC diet-induced liver inflammation and injury in mice.Conclusions These findings support the key role of TLR4 in Kupffer cells in mediating the progression of simple steatosis to NASH, by inducing ROS-dependent activation of XBP-1.