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

Abstract

UNLABELLED:

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.

• Authors: Ying Chen, Yi Yang, Marian L Miller, Dongxiao Shen, Howard G Shertzer, Keith F Stringer, Bin Wang, Scott N Schneider, Daniel W Nebert, Timothy P Dalton
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 45 Issue 5 Pg. 1118-28 (May 2007) ISSN: 0270-9139 [Print] United States
• PMID: 17464988 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Glutamate-Cysteine Ligase
• Glutathione

Topics

• Animals
• Catalytic Domain (physiology)
• Fatty Liver (etiology, genetics, pathology)
• Glutamate-Cysteine Ligase (deficiency)
• Glutathione (deficiency)
• Hepatocytes (metabolism)
• Liver (pathology)
• Liver Failure (genetics, pathology)
• Membrane Potential, Mitochondrial (physiology)
• Mice
• Mice, Knockout
• Mitochondria, Liver (physiology)
• Oxidative Stress