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Am J Pathol:FOXO3具有防止酒精性肝损伤作用

  1. 丙型肝炎
  2. 肝损伤
  3. 转录因子
  4. 酒精

来源:生物谷 2013-11-11 22:34

2013年11月12日讯 /生物谷BIOON/--近日,发表于American Journal of Pathology杂志上的两项最新研究数据表明,转录因子FOXO3具有防止酒精性肝损伤作用。研究人员给予缺乏FOXO3的小鼠酒精,酒精引起小鼠严重肝损伤(类似人类的酒精性肝炎),结果发现FOXO3具有防止酒精性肝损伤作用。此外,研究人员还发现,虽然丙型肝炎病毒(HCV)和酒精两者都能独立地激活FOXO3,但两者组合后反而会抑制FOXO3,同时减少具有细胞保护作用的基因的表达,加剧肝损伤恶化。

新的研究证据表明FOXO转录因子家族在代谢、抗氧化和肝脏细胞死亡中起着关键的作用。Steven A. Weinman博士说:FOXO在肝损伤过程中的作用是复杂的,因为FOXO转录功效具有双重性,或具有细胞保护作用或具有细胞毒性作用。

基于这种新的证据,Weinman博士喂食缺乏FOXO3的小鼠三个星期的酒精。这些小鼠中三分之一的小鼠患上重度肝细胞脂肪变性(脂肪肝细胞浸润),中性粒细胞出现浸润、坏死(这些症状与酒精性肝炎患者相似)。一些老鼠丙氨酸转氨酶(ALT)的水平与对照组相比增加了十倍。

酒精还引起HCV(转基因HCV/Sod2+/-)小鼠模型严重肝损伤。这些动物ALT升高,ICAM - 1的表达增加和caspase 3裂解,出现严重的脂肪变性,小叶内炎症和肝细胞气球样变性。在这些小鼠中,肝损伤程度与线粒体抗氧化酶--超氧化物歧化酶(SOD2)的水平相关(SOD2被认为能保护肝脏免受酒精的伤害)。酒精处理HCV/Sod2+/-小鼠后,小鼠肝细胞细胞质中FOXO3的浓度较高,而对照组小鼠肝细胞细胞核中FOXO3的浓度较高。

Weinman表示:有关酒精性肝病一个重要的悬而未决的问题是,为什么一直以来只有少数喝酒的人(包括那些大量饮酒的人)会发展罹患肝病。对于大多数人来说,肝脏应对酒精存在有效的保护机制。新的研究结果表明,FOXO3就是一种新型的酒精保护因子,但HCV-酒精组合会破坏FOXO3的保护作用。因此,研究人员认为,调控FOXO3途径是一种潜在治疗HCV-酒精诱导肝损伤的方法。
 
在细胞培养实验中,无论是丙型肝炎病毒还是酒精都能增加FOXO3的转录活性。然而,Weinman和他的同事们发现,虽然两者对FOXO3转录活性的影响是相似的,但两者的作用机制不同。例如,丙型肝炎病毒对FOXO3活化的促进作用与FOXO3从细胞质易位到细胞核这一过程有关,但酒精增加FOXO3的转录活性,不伴有FOXO3核易位过程。另一个差异是,丙型肝炎病毒会造成SOD2翻译被miRNA依赖性的抑制,而酒精却不能。

HCV感染和酒精暴露能协同产生效应,协同产生的效应不同于HCV感染或酒精暴露单独产生的效应。Weinman的结论是:FOXO3是一种新颖的酒精保护因子,HCV-酒精组合能打乱FOXO3的保护效应。

在同一期的American Journal of Pathology杂志上,堪萨斯医学中心大学另一团队发表报告称,FOXO3能防止急性乙醇诱导的脂肪变性和肝功能损伤。这项研究表明,FOXO3对于细胞自噬的激活(细胞的降解途径,通过去除受损的线粒体保护酒精性肝损伤)是必要的。给予FOXO3缺陷小鼠急性酒精,相比于野生型小鼠,会诱发更严重的肝损伤,这是由于自噬相关基因表达下降。这两项研究都表明FOXO3具有保护功效。(生物谷Bioon.com)

Hepatitis C and Alcohol Exacerbate Liver Injury by Suppression of FOXO3

Batbayar Tumurbaatar, Irina Tikhanovich, Zhuan Li, Jinyu Ren, Robert Ralston, Sudhakiranmayi Kuravi, Roosevelt Campbell, Gaurav Chaturvedi, Ting-Ting Huang, Jie Zhao, Junfang Hao, Maura O'Neil, and Steven A. Weinman

Hepatitis C virus (HCV) infection exacerbates alcoholic liver injury by mechanisms that include enhanced oxidative stress. The forkhead box transcription factor FOXO3 is an important component of the antioxidant stress response that can be altered by HCV. To test whether FOXO3 is protective for alcoholic liver injury, we fed alcohol to FOXO3-/- mice. After 3 weeks, one third of these mice developed severe hepatic steatosis, neutrophilic infiltration, and >10-fold alanine aminotransferase (ALT) elevations. In cell culture, either alcohol or HCV infection alone increased FOXO3 transcriptional activity and expression of target genes, but the combination of HCV and alcohol together caused loss of nuclear FOXO3 and decreased its transcriptional activity. This was accompanied by increased phosphorylation of FOXO3. Mice expressing HCV structural proteins on a background of reduced expression of superoxide dismutase 2 (SOD2; Sod2+/-) also had increased liver sensitivity to alcohol, with elevated ALT, steatosis, and lobular inflammation. Elevated ALT was associated with an alcohol-induced decrease in SOD2 and redistribution of FOXO3 to the cytosol. These results demonstrate that FOXO3 functions as a protective factor preventing alcoholic liver injury. The combination of HCV and alcohol, but not either condition alone, inactivates FOXO3, causing a decrease in expression of its target genes and an increase in liver injury. Modulation of the FOXO3 pathway is a potential therapeutic approach for HCV-alcohol–induced liver injury.

doi:10.1016/j.ajpath.2013.08.011
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PMID:

Critical Role of FoxO3 in Alcohol-Induced Autophagy and Hepatotoxicity

Hong-Min Ni, Kuo Du, Min You, and Wen-Xing Ding

Autophagy is a lysosomal degradation process that degrades long-lived cellular proteins and damaged organelles as a critical cell survival mechanism in response to stress. We recently reported that acute ethanol induces autophagy, which then reduces ethanol-induced liver injury. However, the mechanisms by which ethanol induces autophagy are not known. In the present study, ethanol treatment significantly increased both mRNA and protein levels of various essential autophagy-related genes in primary cultured mouse hepatocytes and in mouse liver. Both nuclear translocation of FoxO3a and expression of FoxO3a target genes were increased in ethanol-treated primary hepatocytes and mouse liver. Overexpression of a dominant negative form of FoxO3a inhibited ethanol-induced autophagy-related gene expression and enhanced ethanol-induced cell death in primary hepatocytes, which suggests that FoxO3a is a key factor in regulating ethanol-induced autophagy and cell survival. Resveratrol, a well-known SIRT1 agonist, further enhanced ethanol-induced expression of autophagy-related genes, likely via increased deacetylation of FoxO3a. Moreover, acute ethanol–treated Foxo3a-/- mice exhibited decreased autophagy-related gene expression, but enhanced steatosis and liver injury, compared with wild-type mice. FoxO3a thus plays a critical role in ethanol-induced autophagy in mouse liver. Modulating the FoxO3a autophagy pathway may offer novel therapeutic approaches for treating alcoholic liver pathogenesis.

 

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