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

[摘要] Background & Alms 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 similar 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 repopulanon 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 (C) 2010 European Association for the Study of the Liver Published by Elsevier B V All rights reserved

[发布日期] 2010-12-01

[关键词] Glutathione;Conditional knockout;Mitochondria;Steatohepatitis;Liver fibrosis and cirrhosis