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

Authors: Chen, Ying; Johansson, Elisabet; Yang, Yi; Miller, Marian L; Shen, Dongxiao; Orlicky, David J; Shertzer, Howard G; Vasiliou, Vasilis; Nebert, Daniel W; Dalton, Timothy P

Published In J Hepatol, (2010 Dec)

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

PubMed ID: 20810184

MeSH Terms: 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*; Glutamate-Cysteine Ligase/genetics; Glutamate-Cysteine Ligase/metabolism; Glutathione/metabolism; Hepatocytes/drug effects; Hepatocytes/metabolism; Hepatocytes/ultrastructure; Liver Cirrhosis/etiology*; Liver Cirrhosis/genetics; Liver Cirrhosis/metabolism; Liver Cirrhosis/pathology; Liver/drug effects; Liver/metabolism; Liver/pathology; Mice; Mice, Knockout; Microscopy, Electron, Transmission; Mitochondria, Liver/drug effects; Mitochondria, Liver/metabolism; Oxidative Stress/drug effects; RNA, Messenger/genetics; RNA, Messenger/metabolism