Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, Box 1603, One Gustave L. Levy Place, New York, NY 10029, USA.
Free Radic Biol Med. 2012 Sep 1;53(5):1170-80. doi: 10.1016/j.freeradbiomed.2012.06.029. Epub 2012 Jun 27.
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 are 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 were blunted in CYP2E1 KO mice and by the JNK inhibitor in WT mice. The antioxidant N-acetylcysteine decreased the acute alcohol-induced oxidative stress, the 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 JNK1 and JNK2 KO mice as in WT mice; thus either JNK1 or JNK2 per se is sufficient for induction of steatosis by acute alcohol. The results show that acute alcohol elevation of CYP2E1, oxidative stress, and activation of JNK interact to lower autophagy and increase lipogenic SREBP resulting in fatty liver.
binge alcohol drinking 导致肝脂肪变性。最近的研究表明，慢性乙醇诱导的脂肪肝至少部分依赖于 CYP2E1。急性酒精诱导的脂肪变性的机制以及 CYP2E1 是否发挥作用尚不清楚。酒精引起的氧化应激增加会激活 JNK MAP 激酶信号通路，表明 JNK 可能是预防酒精性脂肪变性的靶点。我们使用 CYP2E1 敲除 (KO) 小鼠、JNK 抑制剂以及 JNK1 或 JNK2 敲除小鼠，以测试 CYP2E1、JNK 以及 JNK1 和 JNK2 各自在急性酒精诱导的脂肪变性中的作用。在野生型 (WT) 小鼠中，急性酒精激活 CYP2E1 并增加氧化应激，这反过来又增加了 JNK 信号通路的激活。CYP2E1 KO 小鼠和 WT 小鼠中的 JNK 抑制剂均减轻了急性酒精诱导的脂肪肝和氧化应激。抗氧化剂 N-乙酰半胱氨酸降低了急性酒精诱导的氧化应激、JNK 的激活和脂肪变性，但没有降低 CYP2E1 的激活。急性酒精降低了自噬并增加了 SREBP 的表达，这些作用被 JNK 抑制剂阻断。JNK1 和 JNK2 KO 小鼠的急性酒精诱导的脂肪变性与 WT 小鼠相同；因此，无论是 JNK1 还是 JNK2 本身都足以诱导急性酒精引起的脂肪变性。结果表明，急性酒精升高 CYP2E1、氧化应激和 JNK 激活相互作用，降低自噬并增加脂肪生成 SREBP，导致脂肪肝。
