S-nitrosothiol signaling regulates liver development and improves outcome following toxic liver injury

Cell Rep. 2014 Jan 16;6(1):56-69. doi: 10.1016/j.celrep.2013.12.007. Epub 2014 Jan 2.


Toxic liver injury is a leading cause of liver failure and death because of the organ's inability to regenerate amidst massive cell death, and few therapeutic options exist. The mechanisms coordinating damage protection and repair are poorly understood. Here, we show that S-nitrosothiols regulate liver growth during development and after injury in vivo; in zebrafish, nitric-oxide (NO) enhanced liver formation independently of cGMP-mediated vasoactive effects. After acetaminophen (APAP) exposure, inhibition of the enzymatic regulator S-nitrosoglutathione reductase (GSNOR) minimized toxic liver damage, increased cell proliferation, and improved survival through sustained activation of the cytoprotective Nrf2 pathway. Preclinical studies of APAP injury in GSNOR-deficient mice confirmed conservation of hepatoprotective properties of S-nitrosothiol signaling across vertebrates; a GSNOR-specific inhibitor improved liver histology and acted with the approved therapy N-acetylcysteine to expand the therapeutic time window and improve outcome. These studies demonstrate that GSNOR inhibitors will be beneficial therapeutic candidates for treating liver injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / toxicity
  • Aldehyde Oxidoreductases / metabolism
  • Animals
  • Chemical and Drug Induced Liver Injury / drug therapy*
  • Liver / drug effects*
  • Liver / growth & development
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / metabolism
  • Nitric Oxide / metabolism
  • Nitric Oxide Donors / pharmacology*
  • Nitric Oxide Donors / therapeutic use
  • S-Nitrosothiols / pharmacology*
  • S-Nitrosothiols / therapeutic use
  • Zebrafish
  • Zebrafish Proteins / metabolism


  • NF-E2-Related Factor 2
  • Nitric Oxide Donors
  • S-Nitrosothiols
  • Zebrafish Proteins
  • nfe2l2a protein, zebrafish
  • Nitric Oxide
  • Acetaminophen
  • Aldehyde Oxidoreductases
  • formaldehyde dehydrogenase, glutathione-independent