Liver disease defect identified The energy sensor adenosine monophosphate–activated protein kinase (AMPK) is implicated in liver damage in nonalcoholic steatohepatitis (NASH), a leading cause of liver-associated death in humans. Zhao et al. used mouse models of NASH and samples from human NASH patients to show that AMPK, the activity of which is lost in NASH, phosphorylates the enzyme procaspase-6. In normal liver cells, this modification limits the activation of caspase-6 and the consequent caspase activation cascade that leads to apoptosis. AMPK and caspase-6 may thus provide therapeutic targets for the treatment of NASH. Science, this issue p. 652 Energy sensor kinase AMPK restrains cell death in liver disease. Liver cell death has an essential role in nonalcoholic steatohepatitis (NASH). The activity of the energy sensor adenosine monophosphate (AMP)–activated protein kinase (AMPK) is repressed in NASH. Liver-specific AMPK knockout aggravated liver damage in mouse NASH models. AMPK phosphorylated proapoptotic caspase-6 protein to inhibit its activation, keeping hepatocyte apoptosis in check. Suppression of AMPK activity relieved this inhibition, rendering caspase-6 activated in human and mouse NASH. AMPK activation or caspase-6 inhibition, even after the onset of NASH, improved liver damage and fibrosis. Once phosphorylation was decreased, caspase-6 was activated by caspase-3 or -7. Active caspase-6 cleaved Bid to induce cytochrome c release, generating a feedforward loop that leads to hepatocyte death. Thus, the AMPK–caspase-6 axis regulates liver damage in NASH, implicating AMPK and caspase-6 as therapeutic targets.

中文翻译：

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AMPK-caspase-6 轴控制非酒精性脂肪性肝炎的肝损伤

确定的肝病缺陷能量传感器单磷酸腺苷活化蛋白激酶 (AMPK) 与非酒精性脂肪性肝炎 (NASH) 的肝损伤有关，这是人类肝脏相关死亡的主要原因。赵等人。使用 NASH 的小鼠模型和人类 NASH 患者的样本表明，在 NASH 中失去活性的 AMPK 磷酸化酶 procaspase-6。在正常肝细胞中，这种修饰限制了 caspase-6 的激活以及随后导致细胞凋亡的 caspase 激活级联。因此，AMPK 和 caspase-6 可能为 NASH 的治疗提供治疗靶点。科学，本期第 3 页。652 能量传感器激酶 AMPK 抑制肝病中的细胞死亡。肝细胞死亡在非酒精性脂肪性肝炎 (NASH) 中具有重要作用。能量传感器单磷酸腺苷 (AMP) 活化蛋白激酶 (AMPK) 的活性在 NASH 中受到抑制。肝脏特异性 AMPK 敲除加重了小鼠 NASH 模型中的肝损伤。AMPK 磷酸化促凋亡 caspase-6 蛋白以抑制其活化，从而控制肝细胞凋亡。AMPK 活性的抑制缓解了这种抑制作用，使 caspase-6 在人和小鼠 NASH 中被激活。AMPK 激活或 caspase-6 抑制，即使在 NASH 发作后，也能改善肝损伤和纤维化。一旦磷酸化降低，caspase-6 就会被 caspase-3 或 -7 激活。活性 caspase-6 裂解 Bid 以诱导细胞色素 c 释放，产生导致肝细胞死亡的前馈循环。因此，AMPK-caspase-6 轴调节 NASH 中的肝损伤，暗示 AMPK 和 caspase-6 作为治疗靶点。