ALDH2 Deficiency Promotes Ethanol-Induced Gut Barrier Dysfunction and Fatty Liver in Mice.
ALDH2 Deficiency Promotes Ethanol-Induced Gut Barrier Dysfunction and Fatty Liver in Mice.
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DOI：
10.1111/acer.12777
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发表时间：
2015-08
期刊：
影响因子：
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通讯作者：
Rao RK
中科院分区：
文献类型：
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作者：
Chaudhry KK;Samak G;Shukla PK;Mir H;Gangwar R;Manda B;Isse T;Kawamoto T;Salaspuro M;Kaihovaara P;Dietrich P;Dragatsis I;Nagy LE;Rao RK
乙醛是一种有毒的乙醇代谢物，它会破坏肠上皮屏障功能。乙醛脱氢酶（ALDH）将乙醛解毒成乙酸。亚洲人和美洲原住民的亚群表现出ALDH 2功能缺失突变的多态性。我们评估了ALDH 2缺乏对乙醇诱导的肠上皮紧密连接和粘附连接破坏、肠屏障功能障碍和肝损伤的影响。将野生型和ALDH 2缺陷型小鼠以Lieber-DeCarli饮食喂养（1-6%）4周。通过FITC-菊糖的血浆-管腔通量测量体内肠通透性，通过共聚焦显微镜分析紧密连接和粘附连接完整性，并通过分析血浆转氨酶活性、组织病理学和肝脏甘油三酯评估肝损伤。乙醇喂养升高结肠粘膜乙醛，这是显着更大的ALDH 2缺陷型小鼠。ALDH 2 −/−小鼠的乙醇饮食摄入量急剧减少。因此，本研究仅在野生型和ALDH 2 +/−小鼠中继续进行。乙醇喂养增加了野生型小鼠远端结肠的粘膜菊粉渗透性，但在近端结肠、回肠或空肠中没有。在ALDH 2 +/−小鼠中，乙醇诱导的菊粉在远端结肠的渗透性不仅高于野生型小鼠，而且菊粉在近端结肠、回肠和空肠的渗透性也升高。ALDH 2 +/−小鼠远端结肠中更大的菊粉渗透性与细胞间连接的紧密连接和粘附连接蛋白更严重的重新分布相关。在ALDH 2 +/−小鼠中，但在野生型小鼠中，乙醇喂养导致回肠中紧密连接和粘附连接蛋白的连接分布丧失。组织学、血浆转氨酶和肝脏甘油三酯分析表明，与野生型小鼠相比，ALDH 2 +/−小鼠中乙醇诱导的肝损伤显著更大。这些数据表明，ALDH 2缺乏增强乙醇诱导的肠上皮紧密连接的破坏、屏障功能障碍和肝损伤。
Acetaldehyde, the toxic ethanol metabolite, disrupts intestinal epithelial barrier function. Aldehyde dehydrogenase (ALDH) detoxifies acetaldehyde into acetate. Sub populations of Asians and Native Americans show polymorphism with loss of function mutations in ALDH2. We evaluated the effect of ALDH2 deficiency on ethanol-induced disruption of intestinal epithelial tight junctions and adherens junctions, gut barrier dysfunction and liver injury. Wild type and ALDH2 deficient mice were fed (1–6%) in Lieber-DeCarli diet for 4 weeks. Gut permeability in vivo measured by plasma-to-luminal flux of FITC-inulin, tight junction and adherens junction integrity analyzed by confocal microscopy and liver injury was assessed by analysis of plasma transaminase activity, histopathology and liver triglyceride. Ethanol feeding elevated colonic mucosal acetaldehyde, which was significantly greater in ALDH2 deficient mice. ALDH2−/− mice showed a drastic reduction in the ethanol diet intake. Therefore, this study was continued only in wild type and ALDH2+/− mice. Ethanol feeding elevated mucosal inulin permeability in distal colon, but not in proximal colon, ileum or jejunum of wild type mice. In ALDH2+/− mice, ethanol-induced inulin permeability in distal colon was not only higher than that in wild type mice, but inulin permeability was also elevated in the proximal colon, ileum and jejunum. Greater inulin permeability in distal colon of ALDH2+/− mice was associated with a more severe redistribution of tight junction and adherens junction proteins from the intercellular junctions. In ALDH2+/− mice, but not in wild type mice, ethanol feeding caused a loss of junctional distribution of tight junction and adherens junction proteins in the ileum. Histopathology, plasma transaminases and liver triglyceride analyses showed that ethanol-induced liver damage was significantly greater in ALDH2+/− mice compared to wild type mice. These data demonstrate that ALDH2 deficiency enhances ethanol-induced disruption of intestinal epithelial tight junctions, barrier dysfunction and liver damage.