Eicosapentaenoic acid ameliorates steatollepatitis and hepatocellular carcinoma in hepatocyte-specific Pten-deficient mice
Eicosapentaenoic acid ameliorates steatollepatitis and hepatocellular carcinoma in hepatocyte-specific Pten-deficient mice
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DOI：
10.1016/j.jhep.2008.10.031
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发表时间：
2009-03-01
影响因子：
25.7
通讯作者：
Ohnishi, Hirohide
中科院分区：
文献类型：
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作者：
Ishii, Hajime;Horie, Yasuo;Ohnishi, Hirohide
背景/目的：二十碳五烯酸（EPA）被认为是一种改善脂质代谢和炎症的试剂。肝细胞特异性 Pten 缺陷小鼠表现出类似于非酒精性脂肪性肝炎 (NASH) 的肝脏病变。因此，我们给Pten缺陷小鼠施用EPA来研究NASH的机制。方法：Pten缺陷小鼠被分配到用标准食物喂养的对照组或用添加5％EPA的标准食物喂养的EPA组。 40周时，对每组的肝脏进行处理以测量甘油三酯含量、基因表达分析、蛋白质印迹分析和组织学检查。还测定了血清活性氧（ROS）水平。 40 周和 76 周龄的小鼠被用于肿瘤负荷实验。结果：EPA 改善 Pten 缺陷小鼠的肝脂肪变性是基于 AMPK α 1 介导的 SREBP-1c 表达减少和 PPAR α 表达增加。与对照组相比，EPA 组表现出较轻的慢性肝脏炎症，这是由于 ROS 形成减少以及花生四烯酸与 EPA 的比率显着降低所致。此外，EPA 通过抑制 MAPK 活性、降低油酸与硬脂酸的比例以及减少 ROS 形成，从而抑制 Pten 缺陷小鼠的肝细胞癌 (HCC) 发展。 结论：EPA 改善了 Pten 缺陷小鼠的脂肪性肝炎和 HCC 的发展。 C 2008 欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
Background/Aims: Eicosapentaenoic acid (EPA) has been known as a reagent for improving lipid metabolism and inflammation. Hepatocyte-specific Pten-deficient mice exhibit hepatic lesions analogous to non-alcoholic steatohepatitis (NASH). Therefore, we administered EPA to Pten-deficient mice to investigate the mechanisms of NASH.Methods: Pten-deficient mice were assigned to a control group fed with a standard chow or an EPA group fed with a 5% EPA-supplemented standard chow. At 40 weeks, livers from each group were processed to measure triglyceride content, gene expression analysis, Western blotting analysis, and histological examination. Level of serum reactive oxygen species (ROS) was also determined. Forty- and 76-week-old mice were used in tumor burden experiments.Results: EPA-ameliorated hepatic steatosis in Pten-deficient mice was based on decreased expression of AMPK alpha 1-mediated SREBP-1c and increased PPAR alpha expression. The EPA group exhibited less severe chronic hepatic inflammation compared to the control group, resulting from decreased ROS formation and a dramatically low ratio of arachidonic acid to EPA. Moreover, EPA inhibited development of hepatocellular carcinoma (HCC) in Pten-deficient mice based on an inhibition of MAPK activity and a low ratio of oleic to stealic acid, and a reduction in ROS formation.Conclusions: EPA ameliorated steatohepatitis and development of HCC in Pten-deficient mice. C 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.