美国加州大学圣地亚哥分校Alan R. Saltiel和Peng Zhao团队合作发现单磷酸腺苷（AMP）激活的蛋白激酶（AMPK）-caspase-6轴可控制非酒精性脂肪性肝炎（NASH）的肝损伤。研究于2020年2月7日发表于国际学术期刊《科学》。

肝细胞死亡是NASH主要原因。能量传感器AMPK的活性在NASH中受到抑制。在小鼠NASH模型中，肝脏特异性AMPK敲除加重了肝损伤。AMPK磷酸化促凋亡的caspase-6蛋白抑制其激活，从而使肝细胞凋亡。AMPK活性的抑制解除了这种抑制作用，使caspase-6在人和小鼠NASH中被激活。即使在NASH发作后，AMPK激活或caspase-6抑制作用也可改善肝损伤和纤维化。一旦磷酸化降低，caspase-6将被caspase-3或-7激活。活跃的caspase-6切割Bid以诱导细胞色素c释放，产生前馈环，导致肝细胞死亡。因此，AMPK-caspase-6轴调节NASH中的肝损伤，表明AMPK和caspase-6可作为治疗靶标。

附：英文原文

Title: An AMPK–caspase-6 axis controls liver damage in nonalcoholic steatohepatitis

Author: Peng Zhao, Xiaoli Sun, Cynthia Chaggan, Zhongji Liao, Kai in Wong, Feng He, Seema Singh, Rohit Loomba, Michael Karin, Joseph L. Witztum, Alan R. Saltiel

Issue&Volume: 2020/02/07

Abstract: 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.

DOI: 10.1126/science.aay0542

Source: https://science.sciencemag.org/content/367/6478/652