Severe alcoholic hepatitis (SAH) is a deadly liver disease without an effective medical therapy. Although SAH mortality is known to correlate with hepatic accumulation of immature liver cells, why this occurs and how it causes death are unclear. Here, we demonstrate that expression of epithelial splicing regulatory protein 2 (ESRP2), an RNA-splicing factor that maintains the nonproliferative, mature phenotype of adult hepatocytes, was suppressed in both human SAH and various mouse models of SAH in parallel with the severity of alcohol consumption and liver damage. Inflammatory cytokines released by excessive alcohol ingestion reprogrammed adult hepatocytes into proliferative, fetal-like cells by suppressing ESRP2. Sustained loss of ESRP2 permitted reemergence of a fetal RNA-splicing program that attenuates the Hippo signaling pathway and thus allows fetal transcriptional regulators to accumulate in adult liver. We further showed that depleting ESRP2 in mice exacerbated alcohol-induced steatohepatitis, enabling surviving hepatocytes to shed adult hepatocyte functions and become more regenerative, but threatening overall survival by populating the liver with functionally immature hepatocytes. Our findings revealed a mechanism that explains why liver failure develops in patients with the clinical syndrome of SAH, suggesting that recovery from SAH might be improved by limiting adult-to-fetal reprogramming in hepatocytes.

中文翻译：

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上皮剪接调节蛋白 2 介导的选择性剪接在严重酒精性肝炎中重新编程肝细胞。


严重酒精性肝炎（SAH）是一种致命的肝脏疾病，没有有效的药物治疗方法。尽管已知SAH死亡率与肝脏中未成熟肝细胞的积累相关，但为什么会发生这种情况以及它如何导致死亡尚不清楚。在这里，我们证明，上皮剪接调节蛋白 2 (ESRP2) 是一种维持成年肝细胞非增殖、成熟表型的 RNA 剪接因子，在人类 SAH 和各种 SAH 小鼠模型中，其表达受到抑制，与 SAH 的严重程度平行。饮酒和肝损伤。过量饮酒释放的炎症细胞因子通过抑制 ESRP2 将成年肝细胞重新编程为增殖性胎儿样细胞。 ESRP2 的持续缺失使得胎儿 RNA 剪接程序重新出现，该程序减弱了 Hippo 信号通路，从而允许胎儿转录调节因子在成人肝脏中积累。我们进一步表明，耗尽小鼠中的 ESRP2 会加剧酒精诱导的脂肪性肝炎，使幸存的肝细胞摆脱成年肝细胞功能并变得更具再生性，但由于肝脏中充满了功能不成熟的肝细胞，从而威胁到总体生存。我们的研究结果揭示了一种机制，可以解释为什么 SAH 临床综合征患者会出现肝功能衰竭，这表明可以通过限制肝细胞中成人至胎儿的重编程来改善 SAH 的恢复。