Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver.
Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver.
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DOI：
10.1016/j.freeradbiomed.2012.06.029
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发表时间：
2012-09-01
影响因子：
7.4
通讯作者：
Cederbaum, Arthur I.
中科院分区：
文献类型：
--
作者：
Yang, Lili;Wu, Defeng;Wang, Xiaodong;Cederbaum, Arthur I.
酗酒可诱发肝脂肪变性。最近的研究表明，慢性乙醇诱导的脂肪肝是，至少部分，CYP 2 E1依赖。急性酒精性脂肪变性的机制以及CYP 2 E1是否起作用尚不清楚。酒精增加氧化应激可激活JNK MAP激酶信号通路，提示JNK可能是预防酒精性脂肪变性的靶点。我们使用CYP 2 E1敲除（KO）小鼠（JNK抑制剂）和JNK 1或JNK 2敲除小鼠来测试CYP 2 E1、JNK的作用以及JNK 1和JNK 2在急性酒精诱导的脂肪变性中的个体作用。在野生型（WT）小鼠中，急性酒精激活CYP 2 E1并增加氧化应激，从而增加JNK信号通路的激活。急性酒精诱导的脂肪肝和氧化应激在CYP 2 E1基因敲除小鼠和JNK抑制剂在WT小鼠中被钝化。抗氧化剂N-乙酰半胱氨酸可降低急性酒精诱导的氧化应激、JNK活化和脂肪变性，但不能降低CYP 2 E1活化。急性酒精减少自噬和增加SREBP的表达，JNK抑制剂阻断的影响。急性酒精诱导的脂肪肝在JNK 1或JNK 2 KO小鼠中与WT小鼠相同，因此JNK 1或JNK 2本身足以诱导急性酒精引起的脂肪变性。CYP 2 E1的急性酒精升高、氧化应激和JNK的活化相互作用以降低自噬并增加脂肪生成SREBP，从而导致脂肪肝。
Binge alcohol drinking induces hepatic steatosis. Recent studies showed that chronic ethanol-induced fatty liver was, at least in part, CYP2E1 dependent. The mechanism of acute alcohol induced steatosis and whether CYP2E1 plays any role is still unclear. Increasing oxidative stress by alcohol can activate the JNK MAP kinase signaling pathway, suggesting that JNK might be a target for prevention of alcohol induced steatosis. We used CYP2E1 knockout (KO) mice, a JNK inhibitor, and JNK1 or JNK2 knockout mice to test the role of CYP2E1, JNK, and the individual role of JNK1 and JNK2 in acute alcohol-induced steatosis. In wild type (WT) mice, acute alcohol activates CYP2E1 and increases oxidative stress, which reciprocally increases activation of the JNK signaling pathway. Acute alcohol–induced fatty liver and oxidative stress was blunted in CYP2E1 KO mice and by the JNK inhibitor in WT mice. The antioxidant N-acetylcysteine decreased the acute alcohol induced oxidative stress, activation of JNK and the steatosis but not the activation of CYP2E1. Acute alcohol decreased autophagy and increased expression of SREBP, effects blocked by the JNK inhibitor. Acute alcohol–induced fatty liver was the same in either JNK1 or JNK2 KO mice as WT mice, thus either JNK1 or JNK2 per se is sufficient in induction of steatosis by acute alcohol. acute alcohol elevation of CYP2E1, oxidative stress and activation of JNK interact to lower autophagy and increase lipogenic SREBP resulting in fatty liver.
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影响因子：
13.5
作者：
Lu, Yongke;Zhuge, Jian;Cederbaum, Arthur I.
通讯作者：
Cederbaum, Arthur I.
影响因子：
2.3
作者：
Mansouri, Abdellah;Tarhuni, Arige;Pessayre, Dominique
通讯作者：
Pessayre, Dominique
影响因子：
6.7
作者：
Nishina, Sohji;Korenaga, Masaaki;Hino, Keisuke
通讯作者：
Hino, Keisuke
DOI：
10.1111/j.1530-0277.2010.01239.x
发表时间：
2010-09-01
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Aroor AR;James TT;Jackson DE;Shukla SD
通讯作者：
Shukla SD
影响因子：
5.3
作者：
Liu, J;Minemoto, Y;Lin, AN
通讯作者：
Lin, AN