Institute of Biomedical Research, College of Agriculture and Biology, Liaocheng University, Liaocheng, China.
State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
Life Sci. 2024 Dec 1;358:123166. doi: 10.1016/j.lfs.2024.123166. Epub 2024 Oct 22.
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.
ALD was induced in mice by chronic and binge ethanol feeding (the NIAAA model). Cellular transcriptome was examined by RNA-seq.
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.
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.
过量饮酒会导致酒精性肝病（ALD），这是肝硬化和肝细胞癌的主要致病因素。在本研究中，我们研究了磷脂酶 D2（PLD2）在 ALD 发病机制中的作用。
通过慢性和 binge 乙醇喂养（NIAAA 模型）在小鼠中诱导 ALD。通过 RNA-seq 检查细胞转录组。
RNA-seq 数据集的分析表明，PLD2 的表达在肝组织和 ALD 发病过程中的肝细胞中上调。肝细胞暴露于乙醇处理会导致 PLD2 表达增加。同样，乙醇喂养在小鼠中刺激了肝脏中 PLD2 的表达。相反，肝细胞中的 PLD2 敲低下调了促炎和促脂基因的表达，并抑制了脂质积累。一致地，PLD2 敲低在小鼠中显著改善了 ALD 的发病机制，表现为脂肪变性和肝炎症减轻。RNA-seq 确定了几个受 PLD2 缺乏影响的代谢途径。
我们的数据表明 PLD2 是 ALD 的一种新型调节剂，并表明小分子 PLD2 抑制剂可被视为治疗 ALD 的合理策略。
