AMPK-caspase-6 轴控制非酒精性脂肪性肝炎中的肝损伤。
An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis.
机构信息
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
出版信息
Science. 2020 Feb 7;367(6478):652-660. doi: 10.1126/science.aay0542.
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.
肝细胞死亡在非酒精性脂肪性肝炎（NASH）中起着重要作用。能量传感器腺苷单磷酸（AMP）激活的蛋白激酶（AMPK）的活性在 NASH 中受到抑制。肝特异性 AMPK 敲除加重了 NASH 小鼠模型的肝损伤。AMPK 磷酸化促凋亡半胱氨酸蛋白酶-6 蛋白以抑制其激活，从而抑制肝细胞凋亡。抑制 AMPK 活性可解除这种抑制，使 caspase-6 在人和 NASH 小鼠中激活。即使在 NASH 发生后，AMPK 激活或 caspase-6 抑制也可改善肝损伤和纤维化。一旦磷酸化减少，caspase-6 就会被 caspase-3 或 caspase-7 激活。活性 caspase-6 切割 Bid 以诱导细胞色素 c 释放，形成一个正反馈环，导致肝细胞死亡。因此，AMPK-caspase-6 轴调节 NASH 中的肝损伤，提示 AMPK 和 caspase-6 是治疗靶点。
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