Loss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol.
Loss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol.
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DOI：
10.1053/j.gastro.2016.06.022
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发表时间：
2016-10
期刊：
影响因子：
29.4
通讯作者：
Anania FA
中科院分区：
文献类型：
--
作者：
Rahman K;Desai C;Iyer SS;Thorn NE;Kumar P;Liu Y;Smith T;Neish AS;Li H;Tan S;Wu P;Liu X;Yu Y;Farris AB;Nusrat A;Parkos CA;Anania FA
临床研究表明，肠上皮通透性受损有助于非酒精性脂肪性肝炎（NASH）的发生，但确切机制尚不清楚。编码连接粘附分子A（JAM-A）的基因（F11 r）被破坏的小鼠具有肠上皮通透性缺陷。我们使用这些小鼠来研究肠上皮屏障的破坏如何促成NASH。雄性C57 BL/6（对照）或F11 r −/−小鼠喂食正常饮食或高饱和脂肪、果糖和胆固醇（HFCD）饮食8周。收集肝脏和肠组织，并通过组织学、定量逆转录PCR和流式细胞术进行分析。通过测量对荧光标记的葡聚糖的渗透性来评估小鼠中肠上皮的渗透性。使用16 S rRNA测序分析肠道微生物群。我们还分析了30例非酒精性脂肪性肝病（NAFLD）患者和19例非NAFLD受试者（对照组）接受监测结肠镜检查的近端结肠活检。喂食HFCD而非正常饮食的F11 r −/−小鼠出现严重NASH的组织学和病理学特征，包括脂肪变性、小叶炎症、肝细胞气球样变和纤维化，而喂食HFCD的对照小鼠仅出现中度脂肪变性。有趣的是，在对照组和喂食HFCD的F11 r −/−小鼠之间，体重、肝脏重量与体重之比或葡萄糖稳态没有差异。与对照小鼠或喂食正常饮食的F11 r-/-小鼠相比，在这些小鼠中，肝脏损伤与粘膜炎症、紧密连接破坏和肠上皮对细菌内毒素的渗透性显着增加有关。与对照组小鼠相比，HFCD导致F11 r −/−小鼠的炎症微生物类群显著增加。在喂食HFCD的F11 r −/−小鼠中，口服抗生素或用盐酸司维拉姆隔离细菌内毒素可减轻粘膜炎症并恢复正常的肝脏组织学。NAFLD患者肠粘膜中JAM-A的蛋白和转录水平显著低于非NAFLD患者; JAM-A表达降低与粘膜炎症增加相关。肠上皮通透性缺陷的小鼠在HFCD后比对照小鼠发生更严重的脂肪性肝炎;来自NAFLD患者的结肠组织的JAM-A水平较低，炎症水平高于无NAFLD的受试者。这些发现表明肠上皮屏障功能和微生物生态失调有助于NASH的发展。恢复肠道屏障完整性和操纵肠道微生物群可能被开发为NASH患者的治疗策略。
There is evidence from clinical studies that compromised intestinal epithelial permeability contributes to the development of non-alcoholic steatohepatitis (NASH), but the exact mechanisms are not clear. Mice with disruption of the gene (F11r) encoding junctional adhesion molecule A (JAM-A) have defects in intestinal epithelial permeability. We used these mice to study how disruption of the intestinal epithelial barrier contributes to NASH. Male C57BL/6 (control) or F11r−/− mice were fed a normal diet or a diet high in saturated fat, fructose and cholesterol (HFCD) for 8 weeks. Liver and intestinal tissues were collected and analyzed by histology, quantitative reverse transcription PCR and flow cytometry. Intestinal epithelial permeability was assessed in mice by measuring permeability to fluorescently labeled dextran. The intestinal microbiota were analyzed using 16S rRNA sequencing. We also analyzed biopsies from proximal colon of 30 patients with non-alcoholic fatty liver disease (NAFLD) and 19 subjects without NAFLD (controls) undergoing surveillance colonoscopy. F11r−/− mice fed a HFCD, but not a normal diet, developed histologic and pathologic features of severe NASH including steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis, whereas control mice fed a HFCD developed only modest steatosis. Interestingly, there were no differences in body weight, ratio of liver weight:body weight, or glucose homeostasis between control and F11r−/− mice fed a HFCD. In these mice, liver injury was associated with significant increases in mucosal inflammation, tight junction disruption and intestinal epithelial permeability to bacterial endotoxins, compared with control mice or F11r−/− mice fed a normal diet. The HFCD led to a significant increase in inflammatory microbial taxa in F11r−/− mice, compared with control mice. Administration of oral antibiotics or sequestration of bacterial endotoxins with sevelamer hydrochloride reduced mucosal inflammation and restored normal liver histology in F11r−/− mice fed a HFCD. Protein and transcript levels of JAM-A were significantly lower in the intestinal mucosa of patients with NAFLD than without NAFLD; decreased expression of JAM-A correlated with increased mucosal inflammation. Mice with defects in intestinal epithelial permeability develop more severe steatohepatitis following a HFCD than control mice; colon tissues from patients with NAFLD have lower levels of JAM-A and higher levels of inflammation than subjects without NAFLD. These findings indicate that intestinal epithelial barrier function and microbial dysbiosis contribute to development of NASH. Restoration of intestinal barrier integrity and manipulation of gut microbiota might be developed as therapeutic strategies for patients with NASH.
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