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

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.