Gut inflammation exacerbates hepatic injury in the high-fat diet induced NAFLD mouse: Attention to the gut-vascular barrier dysfunction
Gut inflammation exacerbates hepatic injury in the high-fat diet induced NAFLD mouse: Attention to the gut-vascular barrier dysfunction
复制标题
肠道炎症加剧高脂饮食诱导的 NAFLD 小鼠的肝损伤：关注肠道血管屏障功能障碍。
DOI：
10.1016/j.lfs.2018.08.017
复制
发表时间：
2018-09-15
期刊：
影响因子：
6.1
通讯作者：
Hou, Xiaohua
中科院分区：
文献类型：
--
作者：
Cheng, Chunwei;Tan, Jun;Hou, Xiaohua
目的：临床实践中提出肠道炎症与肝损伤有关。肠道屏障的破坏一直备受关注，但肠血管屏障（GVB）在这一过程中的作用尚不清楚。本研究旨在探讨肠道炎症是否直接导致非酒精性脂肪性肝炎（NASH）的进展，特别是关注GVB功能障碍。主要方法：雄性C57 bl/6小鼠用高脂饮食（HFD）和1%DSS喂养12周。观察结肠炎性损伤和肝脏损伤情况。通过测定GVB对荧光标记葡聚糖（70 kDa）的通透性和质膜囊泡相关蛋白-1（PV 1）的表达来评估GVB功能。结果：DSS组小鼠出现明显的结肠炎，HFD组小鼠结肠炎的发生率明显高于DSS组。HFD + DSS小鼠表现出比HFD组更严重的肝脂肪变性、炎症和纤维化。HFD + DSS小鼠中下调的紧密连接蛋白表明上皮屏障丧失。在HFD + DSS小鼠中，GVB破坏也被证实为对大分子的渗透性增加和内皮PV 1的高表达。因此，在HFD + DSS小鼠中而不是HFD组中证明了潜在升高的血浆内毒素水平和显著增加的TLR 4/TLR 9 mRNA表达。在受损的肠上皮屏障之外，GVB破坏与细菌移位进入可能在NASH的发病机制中起关键作用。
Aims: Gut inflammation has been put forward to be associated with hepatic injury in the clinical practice. The dismantled intestinal barrier was highly concerned, however, largely unknown about the role of gut-vascular barrier (GVB) in this process. This study aimed to investigate if inflamed gut directly contributes to the progression of non-alcoholic steatohepatitis (NASH), especially attention to the GVB dysfunction.Main methods: Male C57bl/6 mice were fed with a high-fat diet (HFD) and 1% DSS for 12 weeks. The colonic inflammatory injury as well as hepatic injury were evaluated. The GVB function was assessed via measuring the permeability to fluorescently-labeled dextran (70 kDa) and the expression of plasmalemma vesicle-associated protein-1 (PV1). Furthermore, the plasma endotoxin level and hepatic TLR4/TLR9 mRNA expression were detected.Key findings: There were evident colitis in DSS-exposed mice, which trend to be more apparent in HFD ones. The HFD + DSS mice exhibited more serious hepatic steatosis, inflammation and fibrosis than HFD groups. The downregulated tight junction protein in HFD + DSS mice indicated loss of epithelial barrier. The GVB disruption were also confirmed with increased permeability to macromolecules and high expression of endothelial PV1 in HFD + DSS mice. Accordingly, potentially elevated plasma endotoxin levels and markedly increased TLR4/TLR9 mRNA expression were demonstrated in HFD + DSS mice rather than HFD groups.Significance: Gut inflammation exacerbates liver injury and fibrosis in HFD mice, which may contribute to the development of NASH. Beyond the damaged intestinal epithelial barrier, GVB disruption with bacterial translocation into may play a key role in the pathogenesis of NASH.