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Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure†

  1. Ying Chen1,
  2. Yi Yang2,
  3. Marian L. Miller1,
  4. Dongxiao Shen3,
  5. Howard G. Shertzer1,
  6. Keith F. Stringer4,
  7. Bin Wang1,
  8. Scott N. Schneider1,
  9. Daniel W. Nebert1,
  10. Timothy P. Dalton1,‡,*

Article first published online: 26 APR 2007

DOI: 10.1002/hep.21635

Issue

Hepatology

Hepatology

Volume 45, Issue 5, pages 1118–1128, May 2007

Additional Information

How to Cite

Chen, Y., Yang, Y., Miller, M. L., Shen, D., Shertzer, H. G., Stringer, K. F., Wang, B., Schneider, S. N., Nebert, D. W. and Dalton, T. P. (2007), Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure. Hepatology, 45: 1118–1128. doi: 10.1002/hep.21635

Author Information

  1. 1

    Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH

  2. 2

    Abbott Laboratories, Abbott Park, IL

  3. 3

    Center for Immunology and Inflammatory Disease and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA

  4. 4

    Department of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH

  1. ‡

    fax: 513-558-0974

*University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, OH. 45267-0056

  1. †

    Potential conflict of interest: Nothing to report.

  2. ‡

    fax: 513-558-0974

Publication History

  1. Issue published online: 26 APR 2007
  2. Article first published online: 26 APR 2007
  3. Manuscript Accepted: 5 FEB 2007
  4. Manuscript Received: 9 JUN 2006

Funded by

  • NIH. Grant Numbers: R01 ES012463, R01 ES10133, P30 ES06096

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Abstract

Oxidative stress is considered to be a critical mediator in liver injury of various etiologies. Depletion of glutathione (GSH), the major antioxidant in liver, has been associated with numerous liver diseases. To explore the specific role of hepatic GSH in vivo, we targeted Gclc, a gene essential for GSH synthesis, so that it was flanked by loxP sites and used the albumin-cyclization recombination (Alb-Cre) transgene to disrupt the Gclc gene specifically in hepatocytes. Deletion within the Gclc gene neared completion by postnatal day (PND)14, and loss of GCLC protein was complete by PND21. Cellular GSH was progressively depleted between PND14 and PND28—although loss of mitochondrial GSH was less severe. Nevertheless, ultrastructural examination of liver revealed dramatic changes in mitochondrial morphology; these alterations were accompanied by striking decreases in mitochondrial function in vitro, cellular ATP, and a marked increase in lipid peroxidation. Plasma liver biochemistry tests from these mice were consistent with progressive severe parenchymal damage. Starting at PND21, livers from hepatocyte-specific Gclc knockout [Gclc(h/h)] mice showed histological features of hepatic steatosis; this included inflammation and hepatocyte death, which progressed in severity such that mice died at approximately 1 month of age due to complications from liver failure. Conclusion: GSH is essential for hepatic function and loss of hepatocyte GSH synthesis leads to steatosis with mitochondrial injury and hepatic failure. (HEPATOLOGY 2007.)

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