磷脂酶 D2 在酒精相关肝病中驱动细胞脂肪毒性和组织炎症。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2024-10-22 DOI:10.1016/j.lfs.2024.123166

Yan Guo , Jichen Li , Xiulian Miao , Hansong Wang , Hailong Ge , Huihui Xu , Jianguo Wang , Yu Wang

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引用次数: 0

摘要

目的：过量饮酒会导致酒精性肝病（ALD），而酒精性肝病是导致肝硬化和肝细胞癌的主要因素。本研究调查了磷脂酶 D2（PLD2）参与 ALD 发病机制的情况：方法和材料：通过长期和大量喂食乙醇诱导小鼠发生 ALD（NIAAA 模型）。主要发现：RNA-seq数据的分析结果表明，在ALD的发病机制中，油脂脂质D2是一个重要的基因：RNA-seq数据集分析表明，在ALD发病过程中，PLD2在肝组织和肝细胞中的表达上调。将肝细胞暴露于乙醇处理会导致 PLD2 表达增加。同样，小鼠摄入乙醇也会刺激肝脏中 PLD2 的表达。相反，敲除肝细胞中的 PLD2 会下调促炎和促脂生成基因的表达，并抑制脂质积累。同样，在小鼠体内敲除 PLD2 能明显改善 ALD 的发病机制，这体现在脂肪变性和肝脏炎症的减轻上。RNA-seq鉴定出了几条受PLD2缺乏影响的代谢通路：我们的数据证明 PLD2 是 ALD 的新型调控因子，并表明小分子 PLD2 抑制剂可被视为治疗 ALD 的合理策略。

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Phospholipase D2 drives cellular lipotoxicity and tissue inflammation in alcohol-associated liver disease

Aims

Excessive alcohol consumption leads to alcoholic liver disease (ALD), a major contributing factor to cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement of phospholipase D2 (PLD2) in the pathogenesis of ALD.

Methods and materials

ALD was induced in mice by chronic and binge ethanol feeding (the NIAAA model). Cellular transcriptome was examined by RNA-seq.

Key findings

Analysis of RNA-seq datasets indicated that PLD2 expression was up-regulated in liver tissues and in hepatocytes during ALD pathogenesis. Exposure of hepatocytes to ethanol treatment led to an increase in PLD2 expression. Similarly, ethanol feeding in mice stimulated PLD2 expression in the liver. On the contrary, PLD2 knockdown in hepatocytes down-regulated expression of pro-inflammatory and pro-lipogenic genes and dampened lipid accumulation. Consistently, PLD2 knockdown in mice significantly ameliorated ALD pathogenesis as evidenced by reduced steatosis and hepatic inflamamation. RNA-seq identified several metabolic pathways that were influenced by PLD2 deficiency.

Significance

Our data demonstrate that PLD2 is a novel regulator of ALD and suggest that small-molecule PLD2 inhibitors can be considered as a reasonable strategy for ALD treatment.

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.