CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis.
CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis.
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DOI：
10.1016/j.freeradbiomed.2013.09.009
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发表时间：
2013-12
影响因子：
7.4
通讯作者：
Song, Byoung-Joon
中科院分区：
文献类型：
--
作者：
Abdelmegeed, Mohamed A.;Banerjee, Atrayee;Jang, Sehwan;Yoo, Seong-Ho;Yun, Jun-Won;Gonzalez, Frank J.;Keshavarzian, Ali;Song, Byoung-Joon
乙醇诱导的细胞色素P450 2 E1（CYP 2 E1）有助于增加慢性酒精暴露模型中的氧化应激和脂肪变性。然而，其在酒精引起的肠漏和肝损伤中的作用尚不清楚。本研究旨在探讨CYP 2 E1在酒精性肠漏中的作用及脂肪性肝炎的发病机制。雌性野生型（WT）和Cyp 2 e1-null小鼠用三种剂量的过量乙醇（WT-EtOH或Cyp 2 e1-null-EtOH）（6 g/kg经口灌胃，间隔12小时）或葡萄糖（阴性对照）处理。仅WT-EtOH的肠组织学显示上皮改变和固有层起泡，而在最后一次乙醇给药后6 h获得的肝脏组织学显示脂肪变性升高，伴有分散的炎性病灶。这些伴随着血清内毒素、肝肠细菌和甘油三酯水平的升高。当WT-EtOH小鼠用CYP 2 E1特异性抑制剂氯甲噻唑和抗氧化剂N-乙酰半胱氨酸处理时，所有这些变化包括肠组织学和肝细胞凋亡，通过TUNEL测定，均显著逆转，这两种抑制剂均抑制包括肠CYP 2 E1在内的氧化标志物。WT-EtOH还表现出血清TNF-α、肝脏细胞因子、CYP 2 E1和脂质过氧化作用含量升高，线粒体超氧化物歧化酶水平降低，醛脱氢酶2活性抑制。在WT-EtOH中观察到肝细胞凋亡增加，促凋亡蛋白水平升高，活性（磷酸化）p-AKT、p-AMPK和过氧化物酶体增殖物激活受体-α（PPAR-α）水平降低，所有这些均参与脂肪代谢和炎症。这些变化在相应的Cyp 2 e1-null-EtOH小鼠中显著减弱。这些数据表明，由酗酒诱导的肠和肝CYP 2 E1似乎在酗酒介导的氮氧化应激增加、肠渗漏、内毒素血症和脂肪代谢改变以及炎症中起关键作用，从而导致肝细胞凋亡和脂肪性肝炎。
Ethanol-inducible cytochrome P450 2E1 (CYP2E1) contributes to increased oxidative stress and steatosis in chronic alcohol-exposure models. However, its role in binge ethanol-induced gut leakiness and hepatic injury is unclear. This study was aimed to investigate the role of CYP2E1 in binge alcohol-induced gut leakiness and the mechanisms of steatohepatitis. Female wild-type (WT) and Cyp2e1-null mice were treated with three doses of binge ethanol (WT-EtOH or Cyp2e1-null-EtOH) (6 g/kg oral gavage at 12-h intervals) or dextrose (negative control). Intestinal histology of only WT-EtOH exhibited epithelial alteration and blebbing of lamina propria while liver histology obtained at 6 h after the last ethanol dose showed elevated steatosis with scattered inflammatory foci. These were accompanied by increased levels of serum endotoxin, hepatic enterobacteria and triglycerides. All these changes including the intestinal histology and hepatic apoptosis, determined by TUNEL assay, were significantly reversed when WT-EtOH mice were treated with the specific inhibitor of CYP2E1 chlormethiazole and the antioxidant N-acetyl-cysteine, both of which suppressed the oxidative markers including intestinal CYP2E1. WT-EtOH also exhibited elevated amounts of serum TNF-α, hepatic cytokines, CYP2E1 and lipid peroxidation with decreased levels of mitochondrial superoxide dismutase and suppressed aldehyde dehydrogenase 2 activity. Increased hepatocyte apoptosis with elevated levels of pro-apoptotic proteins and decreased levels of active (phosphorylated) p-AKT, p-AMPK and peroxisome proliferator-activated receptor-alpha (PPAR-α), all of which are involved in fat metabolism and inflammation, were observed in WT-EtOH. These changes were significantly attenuated in the corresponding Cyp2e1-null-EtOH mice. These data indicate that both intestinal and hepatic CYP2E1 induced by binge alcohol seem critical in the binge alcohol-mediated increased nitroxidative stress, gut leakage, endotoxemia, and altered fat metabolism, and inflammation, contributing to hepatic apoptosis and steatohepatitis.
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影响因子：
25.7
作者：
Butura, Angelica;Nilsson, Kerstin;Ingelman-Sundberg, Magnus
通讯作者：
Ingelman-Sundberg, Magnus
影响因子：
13.5
作者：
Lu, Yongke;Zhuge, Jian;Cederbaum, Arthur I.
通讯作者：
Cederbaum, Arthur I.
DOI：
10.1124/jpet.102.047852
发表时间：
2003-06-01
影响因子：
3.5
作者：
Lambert, JC;Zhou, ZX;Kang, YJ
通讯作者：
Kang, YJ
影响因子：
13.5
作者：
Ewaschuk, Julia;Endersby, Ryan;Madsen, Karen
通讯作者：
Madsen, Karen
影响因子：
7.4
作者：
Abdelmegeed, Mohamed A.;Moon, Kwan-Hoon;Hardwick, James P.;Gonzalez, Frank J.;Song, Byoung-Joon
通讯作者：
Song, Byoung-Joon