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Science. 2020 Feb 7;367(6478):652-660. doi: 10.1126/science.aay0542.

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

Author information

1
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. asaltiel@ucsd.edu pez021@ucsd.edu.
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

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.

PMID:
32029622
DOI:
10.1126/science.aay0542

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