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Cell Metab. 2018 Feb 6;27(2):339-350.e3. doi: 10.1016/j.cmet.2018.01.007.

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

Author information

1
Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA. Electronic address: xinshou.ouyang@yale.edu.
2
Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA.
3
Laboratory of Cardiovascular Physiology and Tissue Injury, NIAAA/NIH, Bethesda, MD 20892, USA.
4
NIAAA, NIH, 5625 Fishers Lane, Bethesda, MD 20892, USA.
5
Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
6
Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
7
Department of Gastroenterology, Saint-Luc Academic Hospital and Institute of Clinical Research, Catholic University of Louvain, Brussels, Belgium.
8
Unidad de Hepatología, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
9
Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA.
10
Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
11
Institute of Translational Hepatology, Beijing 302 Hospital, Beijing 100039, China.
12
Department of Medicine, Gastroenterology, and Hepatology, University of California, Davis, Sacramento, CA, USA.
13
Section of Digestive Diseases, Yale University, New Haven, CT 06520, USA; West Haven Veterans Medical Center, West Haven, CT 06516, USA. Electronic address: wajahat.mehal@yale.edu.

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.

KEYWORDS:

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

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