Although disturbance of the methionine cycle and sequent decrease in hepatic methylation capacity are known to be important factors in the development of alcoholic liver injury, the underlying mechanisms are not fully understood. Here, we investigated the importance of the methylation of protein phosphatase 2A (PP2A) in alcoholic liver disease (ALD). We found that the severity of ethanol-induced liver injury and the extent of demethylation of PP2A catalytic C subunit (PP2Ac) were reduced after treatment with betaine, a methyl donor involved in the methionine-homocysteine cycle. These results suggest that PP2Ac methylation is decreased due to a broad decrease in hepatic methylation capacity after exposure to ethanol. Moreover, we found that the reduction in PP2Ac methylation led to increased degradation of the regulatory Bα subunit, thus promoting the phosphorylation and nuclear exclusion of Forkhead box O1 (FOXO1) and reducing FOXO1 transcriptional activity. Ultimately, the reduced activity of FOXO1 led to increased expression of TXNIP, which caused hepatic lipid accumulation. Our findings suggest that the reduction of PP2A methylation, a result of decrease hepatic methylation capacity, played an important role in ethanol-induced lipid accumulation via down-regulation of PP2A/Bα and FOXO1 phosphorylation.

中文翻译：

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PP2Ac 甲基化降低通过体外和体内 FOXO1 磷酸化促进乙醇诱导的脂质积累

尽管已知甲硫氨酸循环的紊乱和随后肝甲基化能力的降低是酒精性肝损伤发展的重要因素，但其潜在机制尚不完全清楚。在这里，我们研究了蛋白磷酸酶 2A (PP2A) 甲基化在酒精性肝病 (ALD) 中的重要性。我们发现乙醇引起的肝损伤的严重程度和 PP2A 催化 C 亚基 (PP2Ac) 的去甲基化程度在用甜菜碱（一种参与甲硫氨酸 - 高半胱氨酸循环的甲基供体）治疗后降低。这些结果表明 PP2Ac 甲基化由于暴露于乙醇后肝脏甲基化能力的广泛降低而降低。此外，我们发现 PP2Ac 甲基化的减少导致调节性 Bα 亚基的降解增加，从而促进 Forkhead box O1 (FOXO1) 的磷酸化和核排斥并降低 FOXO1 转录活性。最终，FOXO1 活性降低导致 TXNIP 表达增加，从而导致肝脏脂质积累。我们的研究结果表明，PP2A 甲基化的减少是肝脏甲基化能力降低的结果，通过下调 PP2A/Bα 和 FOXO1 磷酸化，在乙醇诱导的脂质积累中发挥了重要作用。