Journal
SCIENCE
Volume 367, Issue 6478, Pages 652-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aay0542
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Funding
- NIH [P42ES010337, UL1TR001442, R01DK106419, P30DK120515, P30DK063491, R01DK076906, R01DK117551, K99HL143277, P01HL088093, R01DK120714]
- AHA [18POST34060088]
- U.S. Department of Defense (DOD) [CA170674P2]
- National Institute of Neurological Disorders and Stroke [P30NS047101]
- Eli Lilly LIFA program
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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.
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