Activation of autophagy attenuates EtOH-LPS-induced hepatic steatosis and injury through MD2 associated TLR4 signaling.
Activation of autophagy attenuates EtOH-LPS-induced hepatic steatosis and injury through MD2 associated TLR4 signaling.
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自噬的激活通过 MD2 相关的 TLR4 信号减弱 EtOH-LPS 诱导的肝脂肪变性和损伤
DOI：
10.1038/s41598-017-09045-z
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发表时间：
2017-08-24
影响因子：
4.6
通讯作者：
Feng W
中科院分区：
文献类型：
--
作者：
Kong X;Yang Y;Ren L;Shao T;Li F;Zhao C;Liu L;Zhang H;McClain CJ;Feng W
自噬是一种降解受损细胞器和蛋白质的保护机制。已知急性酒精暴露会激活肝脏自噬反应，而慢性酒精暴露会减慢自噬体的形成，同时增加肠道源性内毒素。在当前的研究中，我们检查了脂多糖（LPS）给药是否会降低短期酒精治疗小鼠肝脏中的自噬反应，以及雷帕霉素激活自噬是否可以减轻乙醇-LPS诱导的肝脏脂肪变性和损伤。我们证明，十天的酒精喂养会导致肝脏发生 LPS 诱导的脂质积累和肝损伤，并显着增加肝脂肪变性和血清 AST 水平以及肝细胞 NF-κB 激活。 LPS 增加酒精介导的活性氧 (ROS) 形成，同时减少自噬激活。对小鼠施用雷帕霉素可减弱这些有害作用。雷帕霉素的保护作用与 Raw264.7 细胞中细胞 MD2/TLR4 表达和相互作用的减少有关。综上所述，我们的结果表明，增强的肠源性 LPS 会减少酒精暴露引起的肝脏自噬体数量，并且雷帕霉素激活自噬可以防止 EtOH-LPS 诱导的肝损伤，这可能是通过减少巨噬细胞表达和 TLR4/MD2 信号复合物的相互作用来实现的。
Autophagy serves as a protective mechanism to degrade damaged organelles and proteins. Acute alcohol exposure is known to activate the hepatic autophagy response, whereas chronic alcohol exposure slows autophagosome formation along with an elevation of gut-derived endotoxin. In the current study, we examined whether lipopolysaccharide (LPS) administration decreased autophagic response in the liver of mice treated by short-term alcohol and whether activation of autophagy by rapamycin attenuates EtOH-LPS-induced liver steatosis and injury. We demonstrated that ten-day alcohol feeding primed the liver to LPS-induced lipid accumulation and liver injury with significantly increased hepatic steatosis and serum AST level as well as hepatic cellular NF-κB activation. LPS increased alcohol-mediated reactive oxygen species (ROS) formation while reducing autophagy activation. These deleterious effects were attenuated by rapamycin administration in mice. The protective effects of rapamycin are associated with decreased cellular MD2/TLR4 expression and interaction in Raw264.7 cells. Taken together, our results demonstrated that enhanced gut-derived LPS decreases the hepatic autophagosome numbers in response to alcohol exposure, and activation of autophagy by rapamycin protects from EtOH-LPS-induced liver injury, probably through reduced macrophage expression and interaction of TLR4/MD2 signaling complex.
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DOI：
10.1155/2012/234987
发表时间：
2012
期刊：
Evidence-based complementary and alternative medicine : eCAM
影响因子：
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作者：
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DOI：
10.1152/ajpgi.90232.2008
发表时间：
2008-10-01
影响因子：
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作者：
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通讯作者：
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