Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis
Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis
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DOI：
10.1016/j.jhep.2007.04.019
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发表时间：
2007-10-01
影响因子：
25.7
通讯作者：
Wallace, Matthew
中科院分区：
文献类型：
--
作者：
Rivera, Chantal A.;Adegboyega, Patrick;Wallace, Matthew
背景/目的：在动物模型和人类中的研究表明内毒素血症与非酒精性脂肪性肝炎之间存在关联。由于枯否细胞负责清除内毒素，并通过内毒素与Toll样受体4（TLR - 4）相互作用而被激活，我们研究了脂肪性肝炎发生过程中肝脏TLR - 4表达与枯否细胞含量之间的关系。
方法：给雄性C57BL/6、C3H/HouJ和TLR - 4突变型C3H/HeJ小鼠喂食对照饮食或蛋氨酸/胆碱缺乏饮食（MCDD）。在一组C57BL/6小鼠中，通过每周腹腔注射氯膦酸盐脂质体来清除枯否细胞。3周后，测量血清谷丙转氨酶（ALT）活性和门静脉内毒素水平。采用实时定量聚合酶链反应（Real - time PCR）检测TLR - 4、TLR - 2、CD14、MD - 2、转化生长因子β（TGFβ）、肿瘤坏死因子α（TNFα）、CD36、过氧化物酶体增殖物激活受体α（PPAR - α）、肝脏脂肪酸结合蛋白（L - FABP）和Ⅰ型胶原α1的信使核糖核酸（mRNA）表达。
结果：我们在喂食MCDD的野生型小鼠中观察到了脂肪性肝炎的典型组织学证据、门静脉内毒素血症以及TLR - 4表达增强。相比之下，TLR - 4突变型小鼠的损伤和脂质蓄积标志物显著降低。用氯膦酸盐脂质体破坏枯否细胞减轻了脂肪性肝炎的组织学证据，并阻止了TLR - 4表达的增加。
结论：这些发现证明了TLR - 4信号传导的重要性，并强调了TLR - 4与枯否细胞在脂肪性肝炎发病机制中的直接联系。（C）2007年欧洲肝脏研究协会。由爱思唯尔出版集团（Elsevier B.V.）出版。保留所有权利。
Background/Aims: Studies in animal models and humans suggest a link between endotoxemia and non-alcoholic steatohepatitis. Since Kupffer cells are responsible for clearing endotoxin and are activated via endotoxin interaction with Toll-like receptor 4 (TLR-4), we examined the relationship between hepatic TLR-4 expression and Kupffer cell content during the genesis of steatohepatitis.Methods: Male C57BL/6, C3H/HouJ and TLR-4 mutant C3H/HeJ mice were fed control or methionine/choline-deficient diet (MCDD). In one group of C57BL/6 mice, Kupffer cells were depleted by weekly intraperitoneal injections of clodronate liposomes. After 3 weeks, serum ALT activity and portal endotoxin levels were measured. Real-time PCR was used to examine mRNA expression of TLR-4, TLR-2, CD14, MD-2, TGF beta, TNF alpha, CD36, PPAR-alpha, liver fatty acid binding protein (L-FABP) and collagen alpha 1.Results: We observed histological evidence typical of steatohepatitis, portal endotoxemia and enhanced TLR-4 expression in wild type mice fed MCDD. In contrast, injury and lipid accumulation markers were significantly lower in TLR-4 mutant mice. Destruction of Kupffer cells with clodronate liposomes blunted histological evidence of steatohepatitis and prevented increases in TLR-4 expression.Conclusions: These findings demonstrate the importance of TLR-4 signaling and underscore a direct link between TLR-4 and Kupffer cells in the pathogenesis of steatohepatitis. (C) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.