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

@article{Chen2007HepatocytespecificGD,
  title={Hepatocyte‐specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure},
  author={Ying Chen and Yi Yang and Marian L Miller and Dongxiao Shen and Howard G. Shertzer and Keith F. Stringer and Bin Wang and Scott N. Schneider and Daniel W. Nebert and Timothy P. Dalton},
  journal={Hepatology},
  year={2007},
  volume={45}
}
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… Expand
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References

SHOWING 1-10 OF 46 REFERENCES
The ins and outs of mitochondrial dysfunction in NASH.
TLDR
Reducing the incidence of NASH will be a major challenge for hepatologists for the next decade because some genetic polymorphisms can significantly increase the risk of steatohepatitis and that several drugs can prevent or even reverse NASH. Expand
γ‐Glutamyltranspeptidase–deficient knockout mice as a model to study the relationship between glutathione status, mitochondrial function, and cellular function
TLDR
GGT−/− mice exhibit a loss of GSH homeostasis and impaired oxidative phosphorylation, which may be related to the rate of adenosine triphosphate (ATP) formation and subsequently leads to progressive liver injury, which characterizes the diseased state. Expand
Mitochondria in steatohepatitis.
TLDR
In patients with steatosis, mitochondrial ROS may oxidize hepatic fat deposits, as suggested in animal models, and lipid peroxidation products impair the flow of electrons along the respiratory chain, which may cause overreduction of respiratory chain components, further increasing mitochondrial ROS formation and lipidPeroxidation. Expand
Glutathione depleting agents and lipid peroxidation.
  • M. Comporti
  • Chemistry, Medicine
  • Chemistry and physics of lipids
  • 1987
TLDR
In the bromobenzene-induced liver injury loss of protein thiols as well as impairment of mitochondrial and microsomal Ca2+ sequestration activities are related to lipid peroxidation, however, some redox active compounds such as menadione and t-butylhydroperoxide produce direct oxidation of proteinThiols. Expand
Glutathione Metabolism during Aging and in Alzheimer Disease
TLDR
The results suggest that GCL plays a critical role in maintaining GSH homeostasis under both physiological and pathological conditions; decreased GSH content may be involved in AD pathology in humans; and estrogen increases G SH content in mice by multiple mechanisms. Expand
Detoxification of reactive oxygen species by a nonpeptidyl mimic of superoxide dismutase cures acetaminophen‐induced acute liver failure in the mouse
TLDR
The capacity of MnTBAP to abrogate all those alterations suggests that ROS play a role in APAP‐induced apoptosis of hepatocytes, and explains the beneficial effects of Mn TBAP, which could be of interest in AP AP‐induced ALF in humans. Expand
Regulation of hepatic glutathione metabolism and its role in hepatotoxicity.
  • M. Kretzschmar
  • Biology, Medicine
  • Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie
  • 1996
TLDR
Key steps in the regulation of hepatic glutathione (GSH) metabolism are GSH biosynthesis, the GSH-redox-cycle, the cystathionine pathway, and the carrier-mediated export processes. Expand
Inhibition of glutathione synthesis in the newborn rat: a model for endogenously produced oxidative stress.
TLDR
A model for oxidative stress is described in which glutathione (GSH) synthesis is selectively blocked in newborn rats by administration of L-buthionine-(S,R)-sulfoximine (BSO), and closely resembles oxidative stress that occurs in certain human newborns and in other clinical states. Expand
Mechanistic aspects of enhanced lipid peroxidation following glutathione depletion in vivo.
TLDR
These findings are further support of the previous postulate that GSH depletion per se might lead to an increased lipid peroxidation, possibly due to its lack as a part of the cellular defence system against endogenous toxic intermediates. Expand
Dioxin increases reactive oxygen production in mouse liver mitochondria.
TLDR
To the authors' knowledge, this is the first report to show that dioxin increases mitochondrial respiration-dependent reactive oxygen production, which may play an important role in dioxIn-induced toxicity and disease. Expand
...
1
2
3
4
5
...