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

Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure. Research Abstract Details 

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Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure. Abstract Text:

Ying Chen,Yi Yang,Marian L Miller,Dongxiao Shen,Howard G Shertzer,Keith F Stringer,Bin Wang,Scott N Schneider,Daniel W Nebert,Timothy P Dalton,

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 gene neared completion by postnatal day (PND)14, and loss of GCLC protein was complete by PND21. Cellular GSH was progressively depleted between PND14 and PND28-although loss of mitochondrial GSH was less severe. Nevertheless, ultrastructural examination of liver revealed dramatic changes in mitochondrial morphology; these alterations were accompanied by striking decreases in mitochondrial function in vitro, cellular ATP, and a marked increase in lipid peroxidation. Plasma liver biochemistry tests from these mice were consistent with progressive severe parenchymal damage. Starting at PND21, livers from hepatocyte-specific Gclc knockout [Gclc(h/h)] mice showed histological features of hepatic steatosis; this included inflammation and hepatocyte death, which progressed in severity such that mice died at approximately 1 month of age due to complications from liver failure. CONCLUSION: GSH is essential for hepatic function and loss of hepatocyte GSH synthesis leads to steatosis with mitochondrial injury and hepatic failure.

Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure. Publishing Authors By Initials

Y Chen,Y Yang,ML Miller,D Shen,HG Shertzer,KF Stringer,B Wang,SN Schneider,DW Nebert,TP Dalton,

For similar biochemical phenomena, metabolism, and nutrition: metabolism: oxidative stress research abstracts see: biochemical phenomena, metabolism, and nutrition: metabolism: oxidative stress research

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MEDLINE DATE:

Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Hepatology (Baltimore, Md.)

VOLUME: 45

Page Numbers: 1118-28

Journal Abbreviation:

ISSN: 0270-9139

DAY: 3

MONTH: May

YEAR: 2007

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

Number of References:

LANGUAGE: eng

NlmUniqueID: 8302946

Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure. Keywords Mesh Terms:

KEYWORDS: Oxidative Stress

MESH TERMS: physiology

Chemical & Substance for Abstract: Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure. Information

Substance Name: Glutamate-Cysteine Ligase

Registry Number: EC 6.3.2.2

Grant and Affiliation Information for Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure.

AFFILIATION: Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, and Center for Immunology and Inflammatory Disease, Massachusetts General Hospital, Boston, USA.

Country: United States

AGENCY: United States NIEHS

GRANT: R01 ES10133

ACRONYM: ES

MEDLINETA: Hepatology

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