Fat-1 Transgenic Mice With Augmented n3-Polyunsaturated Fatty Acids Are Protected From Liver Injury Caused by Acute-On-Chronic Ethanol Administration.
Fat-1 Transgenic Mice With Augmented n3-Polyunsaturated Fatty Acids Are Protected From Liver Injury Caused by Acute-On-Chronic Ethanol Administration.
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DOI：
10.3389/fphar.2021.711590
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发表时间：
2021
影响因子：
5.6
通讯作者：
Kirpich I
中科院分区：
文献类型：
--
作者：
Warner J;Hardesty J;Song Y;Sun R;Deng Z;Xu R;Yin X;Zhang X;McClain C;Warner D;Kirpich I
酒精相关性肝病（ALD）是全球范围内肝病的主要原因，酒精相关性肝炎（AH）是ALD的一种严重形式，是导致ALD死亡率和发病率的主要原因。许多因素调节ALD发展和进展的易感性，包括营养因素如膳食脂肪酸。我们小组和其他人最近的工作表明，调节膳食或内源性n6-和n3-多不饱和脂肪酸（PUFA）水平可以分别加重或减轻实验性ALD。在当前的研究中，我们询问了内源性n3-PUFA富集在小鼠模型中的作用，该模型使用将n6-PUFA内源性转化为n3-PUFA的转基因fat-1小鼠来概括早期人类AH的特征。向雄性野生型（WT）和fat-1同窝仔提供含乙醇（EtOH，5% v/v）的液体饲料10天，然后在第11天（处死前9 h）通过经口管饲法给予过量EtOH（5 g/kg）。在WT小鼠中，EtOH处理导致肝损伤，如通过显著升高的血浆ALT水平所确定的，而在fat-1小鼠中，EtOH未引起该生物标志物的增加。与配对喂养对照组相比，WT小鼠中也观察到EtOH介导的肝脏中性粒细胞浸润显著增加，但fat-1小鼠未观察到。与WT EtOH激发小鼠相比，fat-1中几种细胞因子和趋化因子（包括派-1）的肝脏表达显著降低。当用脂多糖刺激时，与WT相比，从fat-1小鼠分离的培养的骨髓源性巨噬细胞表达较少的派-1和Cxcl 2（典型的中性粒细胞化学引诱物）mRNA。此外，我们观察到fat-1与WT EtOH喂养小鼠中促炎M1肝组织驻留巨噬细胞（Kupffer细胞，KCs）减少，以及肝T调节细胞增加。总之，我们的数据表明，内源性n3-PUFA富集对急性慢性EtOH暴露引起的肝损伤具有保护作用，这是一种概括人类AH的范例，表明n3-PUFA可能是这种疾病的可行营养辅助治疗。
Alcohol-associated liver disease (ALD) is the leading cause of liver disease worldwide, and alcohol-associated hepatitis (AH), a severe form of ALD, is a major contributor to the mortality and morbidity due to ALD. Many factors modulate susceptibility to ALD development and progression, including nutritional factors such as dietary fatty acids. Recent work from our group and others showed that modulation of dietary or endogenous levels of n6-and n3-polyunsaturated fatty acids (PUFAs) can exacerbate or attenuate experimental ALD, respectively. In the current study, we interrogated the effects of endogenous n3-PUFA enrichment in a mouse model which recapitulates features of early human AH using transgenic fat-1 mice which endogenously convert n6-PUFAs to n3-PUFAs. Male wild type (WT) and fat-1 littermates were provided an ethanol (EtOH, 5% v/v)-containing liquid diet for 10 days, then administered a binge of EtOH (5 g/kg) by oral gavage on the 11th day, 9 h prior to sacrifice. In WT mice, EtOH treatment resulted in liver injury as determined by significantly elevated plasma ALT levels, whereas in fat-1 mice, EtOH caused no increase in this biomarker. Compared to their pair-fed controls, a significant EtOH-mediated increase in liver neutrophil infiltration was observed also in WT, but not fat-1 mice. The hepatic expression of several cytokines and chemokines, including Pai-1, was significantly lower in fat-1 vs WT EtOH-challenged mice. Cultured bone marrow-derived macrophages isolated from fat-1 mice expressed less Pai-1 and Cxcl2 (a canonical neutrophil chemoattractant) mRNA compared to WT when stimulated with lipopolysaccharide. Further, we observed decreased pro-inflammatory M1 liver tissue-resident macrophages (Kupffer cells, KCs), as well as increased liver T regulatory cells in fat-1 vs WT EtOH-fed mice. Taken together, our data demonstrated protective effects of endogenous n3-PUFA enrichment on liver injury caused by an acute-on-chronic EtOH exposure, a paradigm which recapitulates human AH, suggesting that n3-PUFAs may be a viable nutritional adjuvant therapy for this disease.
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影响因子：
5.6
作者：
Hardesty JE;Warner JB;Song YL;Rouchka EC;McClain CJ;Warner DR;Kirpich IA
通讯作者：
Kirpich IA
DOI：
10.1002/hep.31321
发表时间：
2021-03
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Chu S;Sun R;Gu X;Chen L;Liu M;Guo H;Ju S;Vatsalya V;Feng W;McClain CJ;Deng Z
通讯作者：
Deng Z
影响因子：
16.6
作者：
Kindt A;Liebisch G;Clavel T;Haller D;Hörmannsperger G;Yoon H;Kolmeder D;Sigruener A;Krautbauer S;Seeliger C;Ganzha A;Schweizer S;Morisset R;Strowig T;Daniel H;Helm D;Küster B;Krumsiek J;Ecker J
通讯作者：
Ecker J
影响因子：
5.8
作者：
Dixon LJ;Barnes M;Tang H;Pritchard MT;Nagy LE
通讯作者：
Nagy LE
影响因子：
3.1
作者：
Gao, Bei;Lang, Sonja;Schnabl, Bernd
通讯作者：
Schnabl, Bernd