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 language | English (US) |
|---|---|
| Pages (from-to) | 339-350.e3 |
| Journal | Cell Metabolism |
| Volume | 27 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 6 2018 |
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Keywords
- alcohol
- digoxin
- HIF-1α
- liver
- NASH
- pyruvate kinase M2
- ROS
- steatohepatitis
- sterile inflammation
- therapy
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology
Cite this
Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis. / Ouyang, Xinshou; Han, Sheng Na; Zhang, Ji Yuan; Nemeth, Balazs Tamas; Pacher, Pal; Feng, Dechun; Bataller, Ramon; Cabezas, Joaquin; Stärkel, Peter; Caballeria, Joan; Pongratz, Rebecca Le Pine; Cai, Shi Ying; Schnabl, Bernd; Hoque, Rafaz; Chen, Yonglin; Yang, Wei hong; Martinez, Irma Garcia; Wang, Fu Sheng; Gao, Bin; Torok, Natalia J; Kibbey, Richard Glenn; Mehal, Wajahat Zafar.
In: Cell Metabolism, Vol. 27, No. 2, 06.02.2018, p. 339-350.e3.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis
AU - Ouyang, Xinshou
AU - Han, Sheng Na
AU - Zhang, Ji Yuan
AU - Nemeth, Balazs Tamas
AU - Pacher, Pal
AU - Feng, Dechun
AU - Bataller, Ramon
AU - Cabezas, Joaquin
AU - Stärkel, Peter
AU - Caballeria, Joan
AU - Pongratz, Rebecca Le Pine
AU - Cai, Shi Ying
AU - Schnabl, Bernd
AU - Hoque, Rafaz
AU - Chen, Yonglin
AU - Yang, Wei hong
AU - Martinez, Irma Garcia
AU - Wang, Fu Sheng
AU - Gao, Bin
AU - Torok, Natalia J
AU - Kibbey, Richard Glenn
AU - Mehal, Wajahat Zafar
PY - 2018/2/6
Y1 - 2018/2/6
N2 - 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.
AB - 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.
KW - alcohol
KW - digoxin
KW - HIF-1α
KW - liver
KW - NASH
KW - pyruvate kinase M2
KW - ROS
KW - steatohepatitis
KW - sterile inflammation
KW - therapy
UR - http://www.scopus.com/inward/record.url?scp=85044723075&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044723075&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2018.01.007
DO - 10.1016/j.cmet.2018.01.007
M3 - Article
C2 - 29414684
AN - SCOPUS:85044723075
VL - 27
SP - 339-350.e3
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 2
ER -