Oral N-acetylcysteine rescues lethality of hepatocyte-specific Gclc-knockout mice, providing a model for hepatic cirrhosis.
OBJECTIVE
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.
Chen
Ying
Y
Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267, USA. ying.chen@ucdenver.edu
Johansson
Elisabet
E
Yang
Yi
Y
Miller
Marian L
ML
Shen
Dongxiao
D
Orlicky
David J
DJ
Shertzer
Howard G
HG
Vasiliou
Vasilis
V
Nebert
Daniel W
DW
Dalton
Timothy P
TP
D000111:Acetylcysteine / Q000008:administration & dosage*; D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001483:Base Sequence; D016207:Cytokines / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005721:Glutamate-Cysteine Ligase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; D016207:Cytokines; D017931:DNA Primers; D012333:RNA, Messenger; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D000111:Acetylcysteine
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