Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet
Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet
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DOI：
10.1002/hep.21874
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发表时间：
2007-11-01
期刊：
影响因子：
13.5
通讯作者：
Kaneko, Shuichi
中科院分区：
文献类型：
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作者：
Matsuzawa, Naoto;Takamura, Toshinari;Kaneko, Shuichi
最近，非酒精性脂肪性肝炎（NASH）被发现与独立于代谢综合征的心血管疾病事件相关。本研究的目的是研究致动脉粥样硬化（Ath）饮食是否诱导诊断人类NASH所必需的脂肪性肝炎病理，以及胆固醇和甘油三酯如何改变负责氧化应激的肝脏基因表达谱。我们研究了肝脏病理学和血浆和肝脏脂质的小鼠喂养的Ath饮食。用基因芯片和实时聚合酶链反应检测肝脏基因表达谱。Ath饮食诱导血脂异常、脂质过氧化和肝脏中的星状细胞活化，并最终在24周后引起脂肪性肝炎。与现有的动物模型相比，观察到细胞气球样变，这是定义人类NASH的必要组织学特征。在Ath饮食中添加高脂肪成分会引起肝脏胰岛素抵抗，并进一步加速脂肪性肝炎的病理学。一项全球基因表达分析显示，Ath饮食上调了脂肪酸合成、氧化应激、炎症和纤维化基因的肝脏表达水平，而添加高脂肪成分进一步加速了这些基因的表达。相反，高脂肪成分下调肝脏抗氧化酶的基因表达，并可能增加氧化应激。结论：Ath饮食诱导氧化应激和脂肪性肝炎伴细胞气球样变。高脂肪成分诱导胰岛素抵抗，下调抗氧化酶基因，并进一步加重脂肪性肝炎。该模型表明脂质在引起氧化应激和胰岛素抵抗导致脂肪性肝炎中的关键作用。
Recently, nonalcoholic steatohepatitis (NASH) was found to be correlated with cardiovascular disease events independently of the metabolic syndrome. The aim of this study was to investigate whether an atherogenic (Ath) diet induces the pathology of steatohepatitis necessary for the diagnosis of human NASH and how cholesterol and triglyceride alter the hepatic gene expression profiles responsible for oxidative stress. We investigated the liver pathology and plasma and hepatic lipids of mice fed the Ath diet. The hepatic gene expression profile was examined with microarrays and real-time polymerase chain reactions. The Ath diet induced dyslipidemia, lipid peroxidation, and stellate cell activation in the liver and finally caused precirrhotic steatohepatitis after 24 weeks. Cellular ballooning, a necessary histological feature defining human NASH, was observed in contrast to existing animal models. The addition of a high-fat component to the Ath diet caused hepatic insulin resistance and further accelerated the pathology of steatohepatitis. A global gene expression analysis revealed that the Ath diet up-regulated the hepatic expression levels of genes for fatty acid synthesis, oxidative stress, inflammation, and fibrogenesis, which were further accelerated by the addition of a high-fat component. Conversely, the high-fat component down-regulated the hepatic gene expression of antioxidant enzymes and might have increased oxidative stress. Conclusion: The Ath diet induces oxidative stress and steatohepatitis with cellular ballooning. The high-fat component induces insulin resistance, down-regulates genes for antioxidant enzymes, and further aggravates the steatohepatitis. This model suggests the critical role of lipids in causing oxidative stress and insulin resistance leading to steatohepatitis.