Oral N-acetylcysteine rescues lethality of hepatocyte-specific Gclc-knockout mice, providing a model for hepatic cirrhosis.

Abstract

BACKGROUND & AIMS:

Certain liver diseases have been associated with depletion of glutathione (GSH), the major antioxidant in the liver. A recent report about Gclc(h/h) mice with a hepatocyte-specific ablation of Gclc (the gene encoding the catalytic subunit of the rate-limiting enzyme in GSH synthesis) has shown an essential role of GSH in hepatic function. Gclc(h/h) mice develop severe steatosis and die of liver failure within one month, due to ~95% depletion of hepatic GSH; mitochondria are the major affected organelles, displaying abnormal ultrastructure and impaired functioning.

METHODS:

Gclc(h/h) mice were fed with L-N-acetylcysteine (NAC; 10 g/L) in drinking water, starting at postnatal day 18.

RESULTS:

Gclc(h/h) mice were rescued by use of NAC supplementation, and survived until adulthood. NAC replenished the mitochondrial GSH pool and attenuated mitochondrial damage, with accompanying diminished hepatic steatosis; however, abnormal liver biochemical tests, hepatocyte death, and hepatic oxidative stress persisted in the rescued mice. At 50 days of age, the liver from rescued Gclc(h/h) mice started to display characteristics of fibrosis and at age 120 days, macronodular cirrhosis was observed. Immunohistostaining for liver-specific markers as well as the expression profile of hepatic cytokines indicated that the repopulation of hepatocytes in the cirrhotic nodules involved the expansion of oval cells.

CONCLUSIONS:

Replenishment of mitochondrial GSH and restoration of mitochondrial function by NAC prevents mortality caused by the loss of hepatocyte GSH de novo synthesis, allowing steatosis to progress to a chronic stage. Thus, with NAC supplementation, Gclc(h/h) mice provide a model for the development of liver fibrosis and cirrhosis.

• Authors: Ying Chen, Elisabet Johansson, Yi Yang, Marian L Miller, Dongxiao Shen, David J Orlicky, Howard G Shertzer, Vasilis Vasiliou, Daniel W Nebert, Timothy P Dalton
• Journal: Journal of hepatology (J Hepatol) Vol. 53 Issue 6 Pg. 1085-94 (Dec 2010) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 20810184 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antioxidants
• Cytokines
• DNA Primers
• RNA, Messenger
• Glutamate-Cysteine Ligase
• Glutathione
• Acetylcysteine

Topics

• Acetylcysteine (administration & dosage)
• Administration, Oral
• Animals
• Antioxidants (metabolism)
• Base Sequence
• Cytokines (genetics)
• DNA Primers (genetics)
• Disease Models, Animal
• Gene Expression Profiling
• Glutamate-Cysteine Ligase (deficiency, genetics, metabolism)
• Glutathione (metabolism)
• Hepatocytes (drug effects, metabolism, ultrastructure)
• Liver (drug effects, metabolism, pathology)
• Liver Cirrhosis (etiology, genetics, metabolism, pathology)
• Mice
• Mice, Knockout
• Microscopy, Electron, Transmission
• Mitochondria, Liver (drug effects, metabolism)
• Oxidative Stress (drug effects)
• RNA, Messenger (genetics, metabolism)