Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis

Xinshou Ouyang, Sheng Na Han, Ji Yuan Zhang, Balazs Tamas Nemeth, Pal Pacher, Dechun Feng, Ramon Bataller, Joaquin Cabezas, Peter Stärkel, Joan Caballeria, Rebecca Le Pine Pongratz, Shi Ying Cai, Bernd Schnabl, Rafaz Hoque, Yonglin Chen, Wei hong Yang, Irma Garcia Martinez, Fu Sheng Wang, Bin Gao, Natalia J TorokRichard Glenn Kibbey, Wajahat Zafar Mehal

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Sterile inflammation after tissue damage is a ubiquitous response, yet it has the highest amplitude in the liver. This has major clinical consequences, for alcoholic and non-alcoholic steatohepatitis (ASH and NASH) account for the majority of liver disease in industrialized countries and both lack therapy. Requirements for sustained sterile inflammation include increased oxidative stress and activation of the HIF-1α signaling pathway. We demonstrate the ability of digoxin, a cardiac glycoside, to protect from liver inflammation and damage in ASH and NASH. Digoxin was effective in maintaining cellular redox homeostasis and suppressing HIF-1α pathway activation. A proteomic screen revealed that digoxin binds pyruvate kinase M2 (PKM2), and independently of PKM2 kinase activity results in chromatin remodeling and downregulation of HIF-1α transactivation. These data identify PKM2 as a mediator and therapeutic target for regulating liver sterile inflammation, and demonstrate a novel role for digoxin that can effectively protect the liver from ASH and NASH. Ouyang et al. show that the cardiac glycoside digoxin protects against liver disease by modulating the HIF-1α/oxidative stress pathway in sterile inflammation. Digoxin binds PKM2, limiting its availability to regulate transcription of pro-inflammatory genes. This study identifies a novel protective role for digoxin in alcoholic and non-alcoholic steatohepatitis.

Original languageEnglish (US)
Pages (from-to)339-350.e3
JournalCell Metabolism
Volume27
Issue number2
DOIs
StatePublished - Feb 6 2018

Keywords

  • alcohol
  • digoxin
  • HIF-1α
  • liver
  • NASH
  • pyruvate kinase M2
  • ROS
  • steatohepatitis
  • sterile inflammation
  • therapy

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Ouyang, X., Han, S. N., Zhang, J. Y., Nemeth, B. T., Pacher, P., Feng, D., Bataller, R., Cabezas, J., Stärkel, P., Caballeria, J., Pongratz, R. L. P., Cai, S. Y., Schnabl, B., Hoque, R., Chen, Y., Yang, W. H., Martinez, I. G., Wang, F. S., Gao, B., ... Mehal, W. Z. (2018). Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis. Cell Metabolism, 27(2), 339-350.e3. https://doi.org/10.1016/j.cmet.2018.01.007