Increased intestinal permeability in obese mice:: new evidence in the pathogenesis of nonalcoholic steatohepatitis
Increased intestinal permeability in obese mice:: new evidence in the pathogenesis of nonalcoholic steatohepatitis
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DOI：
10.1152/ajpgi.00024.2006
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发表时间：
2007-02-01
影响因子：
4.5
通讯作者：
Martines, Diego
中科院分区：
文献类型：
--
作者：
Brun, Paola;Castagliuolo, Ignazio;Martines, Diego
一小部分患有脂肪肝的病理性肥胖受试者出现坏死性炎症和纤维化的组织学体征，表明肥胖相关肝病（包括非酒精性脂肪性肝炎）的发病机制中存在多种辅助因子。由于一些观察结果已将细菌内毒素与肝损伤联系起来，本研究的目的是确定肥胖对两种肥胖小鼠（瘦素缺乏（ob/ob）和高瘦素血症（db/db）小鼠）肠粘膜完整性和门静脉血内毒素血症的影响。小鼠肠粘膜屏障功能进行了评估，使用Ussing室，而回肠紧密连接蛋白进行了分析，免疫细胞化学和Western印迹分析。循环促炎细胞因子和门静脉血内毒素水平分别通过ELISA和鲎试验测定。用ELISA和定量RT-PCR检测小鼠肝星状细胞（HSC）的炎性和纤维化表型。Ob/ob和db/db小鼠表现出较低的肠阻力，深刻修改的occludin和zonula occludens-1在肠粘膜中的分布，和较高的循环水平的炎性细胞因子和门静脉内毒素血症与瘦对照小鼠相比。此外，从ob/ob和db/db小鼠分离的HSC显示出更高的膜CD 14 mRNA水平和更明显的脂多糖诱导的促炎和纤维化反应比从瘦动物的HSC。总之，遗传性肥胖小鼠表现出增强的肠道通透性，导致门静脉内毒素血症增加，使HSC对细菌内毒素更敏感。我们认为，在代谢综合征，患者可能同样有一个更大的肠粘膜通透性和门静脉血中的脂多糖水平增加，可以有助于肝脏炎症损伤。
A small percentage of pathologically obese subjects with fatty livers develop histological signs of necroinflammation and fibrosis, suggesting a variety of cofactors in the pathogenesis of obesity-related liver diseases including nonalcoholic steatohepatitis. Since several observations have linked bacterial endotoxins to liver damage, the aim of this study was to determine the effect of obesity on intestinal mucosal integrity and portal blood endotoxemia in two strains of obese mice: leptin-deficient (ob/ob) and hyperleptinemic (db/db) mice. Murine intestinal mucosal barrier function was assessed using a Ussing chamber, whereas ileum tight junction proteins were analyzed by immunocytochemistry and Western blot analysis. Circulating proinflammatory cytokines and portal blood endotoxin levels were measured by ELISA and the limulus test, respectively. The inflammatory and fibrogenic phenotype of murine hepatic stellate cells (HSCs) was determined by ELISA and quantitative RT-PCR. Ob/ob and db/db mice showed lower intestinal resistance, profoundly modified distribution of occludin and zonula occludens-1 in the intestinal mucosa, and higher circulating levels of inflammatory cytokines and portal endotoxemia compared with lean control mice. Moreover, HSCs isolated from ob/ob and db/db mice showed higher membrane CD14 mRNA levels and more pronounced lipopolysaccharide-induced proinflammatory and fibrogenic responses than HSCs from lean animals. In conclusion, genetically obese mice display enhanced intestinal permeability leading to increased portal endotoxemia that makes HSCs more sensitive to bacterial endotoxins. We suggest that in metabolic syndrome, patients may likewise have a greater intestinal mucosa permeability and increased lipopolysaccharide levels in portal blood that can contribute to the liver inflammatory damage.