Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine
Robert Hanczko, … , Steve K. Landas, Andras Perl
Robert Hanczko, … , Steve K. Landas, Andras Perl
Published May 11, 2009
Citation Information: J Clin Invest. 2009;119(6):1546-1557. https://doi.org/10.1172/JCI35722.
View: Text | PDF
Research Article Gastroenterology

Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine

  • Text
  • PDF
Abstract

Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1–/– and Taldo1+/– mice spontaneously developed HCC, and Taldo1–/– mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1–/– livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced β-catenin phosphorylation and enhanced c-Jun expression in Taldo1–/– livers reflected adaptation to oxidative stress. Taldo1–/– hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1–/– mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency.

Authors

Robert Hanczko, David R. Fernandez, Edward Doherty, Yueming Qian, Gyorgy Vas, Brian Niland, Tiffany Telarico, Adinoyi Garba, Sanjay Banerjee, Frank A. Middleton, Donna Barrett, Maureen Barcza, Katalin Banki, Steve K. Landas, Andras Perl

×

Figure 1

Spontaneous development of dysplastic nodules, cirrhosis, and HCC in Taldo1–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Spontaneous development of dysplastic nodules, cirrhosis, and HCC in Tal...
(A) Dysplastic nodules and cirrhosis in Taldo1–/– (–/–) mice. Macroscopic and microscopic images of 52-week-old Taldo1–/– mouse 20M stained with H&E and Klatskin trichrome stain. Arrow denotes inflammatory cells surrounding nodules (N). Klatskin trichrome staining of the liver showed interstitial deposition of collagen (blue). Hepatocytes within the nodules were avidly stained red. Original magnification, left to right: ×100, ×40, ×40. (B) Macroscopic images of HCC in a 74-week-old (931F) and an 82 week-old (1266F) Taldo1–/– mice, and microscopic images of steatosis, dysplasia, mitotic figures (arrows), and hepatoma in 74-week-old Taldo1–/– mouse 931F. Original magnification, left to right: ×100, ×100, ×200.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts