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

• Published in: Science (American Association for the Advancement of Science) Vol. 367; no. 6478; pp. 652 - 660
• Main Authors: Zhao, Peng, Sun, Xiaoli, Chaggan, Cynthia, Liao, Zhongji, in Wong, Kai, He, Feng, Singh, Seema, Loomba, Rohit, Karin, Michael, Witztum, Joseph L., Saltiel, Alan R.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 07.02.2020
• Subjects: Activation; Adenosine; Adenosine kinase; Adenosine monophosphate; AMP; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animal models; Animals; Apoptosis; Apoptosis - genetics; Caspase 3 - metabolism; Caspase 6 - metabolism; Caspase 7 - metabolism; Caspase Inhibitors - pharmacology; Caspase Inhibitors - therapeutic use; Caspase-3; Caspase-6; Cell death; Cytochrome c; Cytochromes; Damage; Disease control; Enzyme Activation; Fibrosis; Hepatocytes; Hepatocytes - enzymology; Hepatocytes - pathology; Humans; Inhibition; Kinases; Liver; Liver - enzymology; Liver - pathology; Liver diseases; Mice; Mice, Knockout; Mortality; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - enzymology; Non-alcoholic Fatty Liver Disease - pathology; Phosphates; Phosphorylation; Protein kinase; Proteins; Therapeutic applications
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aay0542

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.