Dietary Linoleic Acid and Its Oxidized Metabolites Exacerbate Liver Injury Caused by Ethanol via Induction of Hepatic Proinflammatory Response in Mice.
Dietary Linoleic Acid and Its Oxidized Metabolites Exacerbate Liver Injury Caused by Ethanol via Induction of Hepatic Proinflammatory Response in Mice.
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DOI：
10.1016/j.ajpath.2017.06.008
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发表时间：
2017-10
期刊：
影响因子：
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通讯作者：
D. Warner;Huilin Liu;M. Miller;C. Ramsden;B. Gao;A. Feldstein;Susanne Schuster;C. McClain;I. Kirpich
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文献类型：
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作者：
D. Warner;Huilin Liu;M. Miller;C. Ramsden;B. Gao;A. Feldstein;Susanne Schuster;C. McClain;I. Kirpich
酒精性肝病是一个主要的人类健康问题，在美国和世界范围内导致显著的发病率和死亡率。膳食脂肪在酒精性肝病的发病机制中起着重要作用。在此，我们测试了以下假设：乙醇和富含亚油酸（LA）的饮食组合导致氧化LA代谢物（OXLAM）的产生增加，特别是9-和13-羟基十八碳二烯酸（HODE），其有助于肝脏促炎反应，加剧肝损伤。给小鼠喂食不饱和脂肪（LA含量高）或饱和脂肪饮食（分别为USF和SF），含或不含乙醇，持续10天，然后单次狂饮乙醇。与SF+乙醇相比，喂食USF+乙醇的小鼠血浆丙氨酸转氨酶水平升高，肝脏脂肪变性、氧化应激和炎症增强。9-和13-HODE的血浆和肝脏水平增加，以响应USF+乙醇喂养。我们证明，主要是9-HODE，而不是13-HODE，诱导几种促炎细胞因子在体外表达RAW 264.7巨噬细胞。最后，花生四烯酸15-脂氧合酶（一种参与LA氧化和OXLAM生产的主要酶）的缺乏减弱了USF+乙醇喂养引起的肝损伤和炎症，但对肝脂肪变性没有影响。这项研究表明，OXLAM介导的诱导巨噬细胞中的促炎反应是从酒精诱导的脂肪变性进展为酒精性脂肪性肝炎的潜在机制之一。
Alcoholic liver disease is a major human health problem leading to significant morbidity and mortality in the United States and worldwide. Dietary fat plays an important role in alcoholic liver disease pathogenesis. Herein, we tested the hypothesis that a combination of ethanol and a diet rich in linoleic acid (LA) leads to the increased production of oxidized LA metabolites (OXLAMs), specifically 9- and 13-hydroxyoctadecadienoic acids (HODEs), which contribute to a hepatic proinflammatory response exacerbating liver injury. Mice were fed unsaturated (with a high LA content) or saturated fat diets (USF and SF, respectively) with or without ethanol for 10 days, followed by a single binge of ethanol. Compared to SF+ethanol, mice fed USF+ethanol had elevated plasma alanine transaminase levels, enhanced hepatic steatosis, oxidative stress, and inflammation. Plasma and liver levels of 9- and 13-HODEs were increased in response to USF+ethanol feeding. We demonstrated that primarily 9-HODE, but not 13-HODE, induced the expression of several proinflammatory cytokinesin vitroin RAW264.7 macrophages. Finally, deficiency of arachidonate 15-lipoxygenase, a major enzyme involved in LA oxidation and OXLAM production, attenuated liver injury and inflammation caused by USF+ethanol feeding but had no effect on hepatic steatosis. This study demonstrates that OXLAM-mediated induction of a proinflammatory response in macrophages is one of the potential mechanisms underlying the progression from alcohol-induced steatosis to alcoholic steatohepatitis.