@article{e9659c32ee7641a69ea577ae7e7d44e6,
title = "An AMPK–caspase-6 axis controls liver damage in nonalcoholic steatohepatitis",
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.",
author = "Peng Zhao and Xiaoli Sun and Cynthia Chaggan and Zhongji Liao and Wong, {Kai in} and Feng He and Seema Singh and Rohit Loomba and Michael Karin and Witztum, {Joseph L.} and Saltiel, {Alan R.}",
note = "Funding Information: We thank S. J. Morrison at the University of Texas Southwestern and K. Inoki at the University of Michigan for sharing AMPKa1 and a2 floxed mice and University of California, San Diego (UCSD) histology core for histology study. This work was supported by NIH P30DK063491, R01DK076906, and R01DK117551 to A.R.S.; NIH K99HL143277 to P.Z.; AHA 18POST34060088 to X.S.; NIH P01HL088093 to J.L.W.; NIH R01DK120714 to M.K.; NIH P42ES010337, UL1TR001442, R01DK106419, and P30DK120515 and U.S. Department of Defense (DOD) CA170674P2 to R.L.; and National Institute of Neurological Disorders and Stroke P30NS047101 to the UCSD microscopy core. F.H. was supported by the Eli Lilly LIFA program. Publisher Copyright: {\textcopyright} 2020 American Association for the Advancement of Science. All rights reserved.",
year = "2020",
month = feb,
day = "7",
doi = "10.1126/science.aay0542",
language = "English (US)",
volume = "367",
pages = "652--660",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6478",
}