白藜芦醇介导的铁过载收购和遗传小鼠模型的治疗效果肝

StephenW

Resveratrol mediates therapeutic hepatic effects in acquired and genetic murine models of iron-overload

    Subhash K. Das1, Jessica DesAulniers1, Jason R. B. Dyck3, Zamaneh Kassiri2 andGavin Y. Oudit1,2,*

DOI: 10.1111/liv.12893

This article is protected by copyright. All rights reserved.

Issue
Cover image for Vol. 35 Issue 7
Liver International


    1    Department of Medicine, University of Alberta, Edmonton, Canada
    2   Department of Physiology, University of Alberta, Edmonton, Canada
    3    Department of Pediatrics and Pharmacology, University of Alberta, Edmonton, Canada

* Address for Correspondence:
Gavin Y. Oudit, MD, PhD, FRCP(C)
Department of Medicine, Faculty of Medicine and Dentistry
University of Alberta, Edmonton,
Alberta, T6G 2S2, Canada
Phone: 780-407-8569; Fax: 780-407- 6452
[email protected]

    This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/liv.12893



    Iron-overload;lipid peroxidation;hepatic fibrosis;inflammation;oxidative stress;resveratrol

Abstract
Background and Aims

Abnormal iron metabolism and hepatic iron-overload is a major cause of liver injury and in the development of chronic liver diseases. Iron-overload mediated liver disease leads to end-stage cirrhosis and/or hepatocellular carcinoma.
Methods

Using a genetic hemochromatosis (hemojuvelin knockout mice) and non-genetic (secondary iron-overload) murine models of hepatic iron-overload we elucidated the mechanism of hepatic iron injury and the therapeutic effects of resveratrol.
Results

Hepatic iron-overload was associated with hepatosplenomegaly, increased oxidative stress, hepatic fibrosis, and inflammation, and a pro-apoptotic state which was markedly corrected by resveratrol therapy. Importantly our aging studies with the hemojuvelin knockout mice showed advanced liver disease in association with steatosis in the absence of a diabetic state which recapitulates the essential pathological features seen in clinical iron-overload. Chronic hepatic iron-overload showed increased nuclear localization of acetylated Forkhead fox-O-1 (FoxO1) transcription factor while resveratrol dietary intervention reversed the acetylation of FoxO1 in association with increased SIRT1 levels which together with its pleotropic antioxidant properties are likely key mechanisms of its therapeutic action. Importantly, resveratrol treatment did not affect the degree of hepatic iron-overload but rather direct protects the liver from iron-mediated injury.
Conclusions

Our findings illustrate a novel and definitive therapeutic action of resveratrol and represent an economically feasible therapeutic intervention to treat hepatic iron-overload and liver disease.

This article is protected by copyright. All rights reserved.

StephenW

白藜芦醇介导的铁过载收购和遗传小鼠模型的治疗效果肝

    苏巴K. DAS1，杰西卡DesAulniers1，杰森RB Dyck3，Zamaneh Kassiri2 andGavin Y. Oudit1,2，*

DOI：10.1111 / liv.12893

这篇文章是受版权保护的。版权所有。

问题
封面图片卷。 35第7期
肝国际


    医药，阿尔伯塔大学，加拿大埃德蒙顿的1系
    生理学，阿尔伯塔大学，埃德蒙顿，加拿大2部
    儿科和药理学，阿尔伯塔大学，加拿大埃德蒙顿的3系

*通讯地址：
加文Y. Oudit，博士，FRCP（C）
医学系，医学与牙科学院
阿尔伯塔省埃德蒙顿大学，
艾伯塔省，T6G 2S2，加拿大
电话：780-407-8569;传真：780-407- 6452
[email protected]

    这篇文章已被接受发表，并经过充分的同行评审，但经过审稿，排版，分页和校对过程中，这可能会导致这个版本和记录的版本之间的差异一直没有。请引用这篇文章的DOI：10.1111 / liv.12893



    铁过载;脂质过氧化;肝纤维化;炎症;氧化应激;白藜芦醇

抽象
背景和目的

异常铁代谢和肝铁超负荷是肝损伤和慢性肝脏疾病的发展的一个重要原因。铁超负荷介导的肝病导致终末期肝硬化和/或肝细胞癌。
方法

使用遗传性血色病（血幼素敲除小鼠）和非遗传（二次铁超负荷）鼠肝铁超负荷的模型，我们阐明的肝脏铁损伤和白藜芦醇的治疗作用的机制。
结果

肝铁超负荷与肝脾肿大，氧化应激增加，肝纤维化和炎症，以及促凋亡状态，这显着白藜芦醇疗法校正。重要的是我们的老化研究与血幼素敲除小鼠表现出晚期肝病与脂肪在没有糖尿病状态，概括见于临床铁超负荷的基本病理特征关联。慢性肝铁超负荷显示增加的乙酰叉头狐-​​O-1（FoxO1的）转录因子的核定位而白藜芦醇饮食干预逆转的FoxO1的相关联的乙酰化与增加SIRT1的水平这连同其pleotropic抗氧化性能是可能的关键机制其治疗作用。重要的是，白藜芦醇治疗不影响肝脏铁过载的程度，而是直接可防止铁介导的损伤的肝脏。
结论

我们的研究结果说明了一种新的和白藜芦醇的决定性的治疗作用，并代表一种经济上可行的治疗介入治疗肝脏铁过载和肝病。

这篇文章是受版权保护的。版权所有。