Kudo Hiroshi, Takahara Terumi, Yata Yutaka, Kawai Kengo, Zhang Wei, Sugiyama Toshiro
Third Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
J Hepatol. 2009 Jul;51(1):168-75. doi: 10.1016/j.jhep.2009.02.032. Epub 2009 May 3.
BACKGROUND/AIMS: Endogenous gut-derived bacterial endotoxins have been implicated as an important cofactor in the pathogenesis of liver injury, although their contribution to the progression of non-alcoholic steatohepatitis (NASH) remains unclear.
Male C57BL/6 mice were fed a methionine-choline-deficient (MCD) diet or a standard diet for 17 days, following which they were injected with lipopolysaccharide (LPS) intraperitoneally and sacrificed after 6h. In an in vitro experiment, RAW264.7 cells, a mouse macrophage cell line, and primary mouse hepatocytes were co-treated with hydrogen peroxide (H(2)O(2)) and LPS or tumour necrosis factor (TNF)-alpha.
Compared to the control mice, LPS treatment significantly increased hepatic TNF-alpha production in MCD mice. LPS also significantly increased TUNEL-positive cells, which were especially observed in the perivenular area. The apoptotic change was inhibited by co-treatment with a neutralizing anti-mouse TNF receptor antibody or pentoxifylline. In an in vitro experiment, treatment with H(2)O(2) synergistically enhanced LPS-induced TNF-alpha production in RAW264.7 cells, accompanied by an up-regulation of CD14 mRNA. Moreover, co-treatment with TNF-alpha- and H(2)O(2)-induced apoptosis in primary hepatocytes, although neither TNF-alpha nor H(2)O(2) could do so independently.
LPS up-regulated TNF-alpha production, which induced hepatocyte apoptosis in a murine NASH model. LPS may play a key role in the pathogenesis of NASH.
背景/目的：内源性肠道来源的细菌内毒素被认为是肝损伤发病机制中的一个重要辅助因素，尽管其在非酒精性脂肪性肝炎（NASH）进展中的作用仍不清楚。
雄性C57BL/6小鼠分别给予蛋氨酸-胆碱缺乏（MCD）饮食或标准饮食17天，之后腹腔注射脂多糖（LPS），6小时后处死。在体外实验中，将小鼠巨噬细胞系RAW264.7细胞和原代小鼠肝细胞与过氧化氢（H₂O₂）和LPS或肿瘤坏死因子（TNF）-α共同处理。
与对照小鼠相比，LPS处理显著增加了MCD小鼠肝脏TNF-α的产生。LPS还显著增加了TUNEL阳性细胞，尤其在肝小叶中央静脉周围区域观察到。用中和性抗小鼠TNF受体抗体或己酮可可碱共同处理可抑制凋亡变化。在体外实验中，H₂O₂处理协同增强了RAW264.7细胞中LPS诱导的TNF-α产生，并伴有CD14 mRNA的上调。此外，TNF-α和H₂O₂共同处理诱导原代肝细胞凋亡，尽管单独的TNF-α或H₂O₂都不能诱导凋亡。
在小鼠NASH模型中，LPS上调TNF-α的产生，进而诱导肝细胞凋亡。LPS可能在NASH的发病机制中起关键作用。
