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Chronic high-dosage fish oil exacerbates gut–liver axis injury in alcoholic steatohepatitis in mice: the roles of endotoxin and IL-4 in Kupffer cell polarization imbalance
Toxicology Research ( IF 2.1 ) Pub Date : 2017-07-07 00:00:00 , DOI: 10.1039/c7tx00037e
Xiao-Jun Li 1, 2, 3, 4, 5 , Yun-Mei Mu 1, 2, 3, 4, 5 , Qiu-Fang Qin 1, 2, 3, 4, 5 , Zi-Xuan Zeng 1, 2, 3, 4, 5 , Yu-Sang Li 1, 2, 3, 4, 5 , Wei Kevin Zhang 1, 2, 3, 4, 5 , He-Bin Tang 1, 2, 3, 4, 5 , Gui-Hua Tian 5, 6, 7, 8, 9 , Hong-Cai Shang 5, 6, 7, 8, 9
Affiliation  

In the present study, intestinal tight junctions (TJs) and Kupffer cell polarization were investigated in an alcoholic steatohepatitis (ASH) mouse model to uncover the potential side effects of overexposure to fish oil or omega-3 fatty acids. The mice were fed ad libitum with a liquid diet containing ethanol and fish oil. In the meantime, ethanol was given every 5–7 days by gavage to simulate binge drinking. After the 7th binge, steatosis, necrosis, inflammatory infiltration, and bridging fibrosis were observed in the liver by histological staining. After the 13th binge, the inducers, markers and other downstream genes/proteins of the Kupffer cell M1/M2 phenotype in the liver, serum, and small intestine were analysed. The results suggested that a chronic high dosage of fish oil alone reduced the mRNA levels of most genes tested and showed a tendency to damage the intestinal zonula occludens-1 localization and reduce the number of M2 Kupffer cells. Meanwhile, the combination of fish oil and ethanol damaged the intestinal TJs, resulting in an increased endotoxin level in the liver. Gut-derived endotoxin polarized Kupffer cells to the M1 phenotype, whereas the number of cells with the M2 phenotype (markers: CD163 and CD206) was decreased. Interleukin-4 (IL-4), an M2 Kupffer cell inducer, was also decreased. Moreover, in vitro experiments showed that IL-4 reversed eicosapentaenoic acid-induced CD163 and CD206 mRNA suppression in RAW 264.7 cells. Overall, our results showed that a chronic high dosage of fish oil exacerbated gut–liver axis injury in alcoholic liver disease in mice, and endotoxin/IL-4-induced Kupffer cell polarization imbalance might play an important role in that process.

中文翻译:

慢性高剂量鱼油加重了小鼠酒精性脂肪性肝炎的肠肝轴损伤:内毒素和IL-4在库普弗细胞极化失衡中的作用

在本研究中,在酒精性脂肪性肝炎(ASH)小鼠模型中研究了肠道紧密连接(TJs)和Kupffer细胞极化,以发现过度暴露于鱼油或omega-3脂肪酸的潜在副作用。随意给小鼠喂食含有乙醇和鱼油的流质饮食。同时,每5-7天通过管饲法给予乙醇以模拟暴饮暴饮。第7暴饮暴食后,通过组织学染色在肝脏中观察到脂肪变性,坏死,炎性浸润和桥接纤维化。13日之后暴饮暴食,肝,血清和小肠中的库普弗细胞M1 / M2表型的诱导剂,标记和其他下游基因/蛋白质进行了分析。结果表明,单独长期服用高剂量鱼油会降低大多数测试基因的mRNA水平,并显示出损害肠道小带闭塞1定位并减少M2 Kupffer细胞数量的趋势。同时,鱼油和乙醇的结合会破坏肠道TJ,导致肝脏内毒素水平升高。肠源性内毒素使库普弗细胞极化为M1表型,而具有M2表型的细胞数量(标记:CD163和CD206)减少。M2 Kupffer细胞诱导剂白细胞介素4(IL-4)也降低了。而且,在体外实验表明,IL-4可以逆转二十碳五烯酸诱导的RAW 264.7细胞中CD163CD206 mRNA的抑制。总体而言,我们的结果表明,长期高剂量鱼油加重了小鼠酒精性肝病中的肠肝轴损伤,内毒素/ IL-4诱导的库普弗细胞极化失衡可能在该过程中起重要作用。
更新日期:2017-08-03
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