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

  • Science. 2020 Feb 7;367(6478):652-660. doi: 10.1126/science.aay0542.
Peng Zhao  #  1 ,  Xiaoli Sun  #  2 ,  Cynthia Chaggan  2 ,  Zhongji Liao  2 ,  Kai In Wong  2 ,  Feng He  3 ,  Seema Singh  4 ,  Rohit Loomba  4 ,  Michael Karin  3 ,  Joseph L Witztum  2 ,  Alan R Saltiel  1  3
Affiliations
  • 1. Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. [email protected] [email protected].
  • 2. Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • 3. Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • 4. NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • # Contributed equally.
PMID: 32029622 DOI: 10.1126/science.aay0542
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.