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PMID: 12808106 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Nrf1 is critical for redox balance and survival of liver cells during development.

Molecular and cellular biology ·Vol. 23 ·No. 13 ·2003-07-00 ·Pages 4673-86

Chen L, Kwong M, Lu R, Ginzinger D, Lee C, Leung L, Chan JY

Abstract

The Nrf1 transcription factor belongs to the CNC subfamily of basic leucine zipper proteins. Knockout of Nrf1 is lethal in mouse embryos, but nothing is known about the cell types that absolutely require its function during development. We show by chimera analysis that Nrf1 is essential for the hepatocyte lineage. Mouse embryonic stem cells lacking Nrf1 developed normally and contributed to most tissues in adult chimeras where Nrf1 is normally expressed. Nrf1-deficient cells contributed to fetal, but not adult, liver cells. Loss of Nrf1 function resulted in liver cell apoptosis in late-gestation chimeric fetuses. Fetal livers from mutant embryos exhibited increased oxidative stress and impaired expression of antioxidant genes, and primary cultures of nrf1(-/-) fetal hepatocytes were sensitive to tert-butyl hydroperoxide-induced cell death, suggesting that impaired antioxidant defense may be responsible for the apoptosis observed in the livers of chimeric mice. In addition, cells deficient in Nrf1 were sensitized to the cytotoxic effects of tumor necrosis factor (TNF). Our results provide in vivo evidence demonstrating an essential role of Nrf1 in the survival of hepatocytes during development. Our results also suggest that Nrf1 may promote cell survival by maintaining redox balance and protecting embryonic hepatocytes from TNF-mediated apoptosis during development.

MeSH Terms
Animals Antioxidants/metabolism Apoptosis Caspase 3 Caspases/metabolism Cell Death Cell Division Cell Lineage Cell Survival Cells, Cultured DNA-Binding Proteins/metabolism,physiology Dose-Response Relationship, Drug Embryo, Mammalian/cytology Fibroblasts/metabolism Glutathione/metabolism Hepatocytes/cytology,metabolism Lac Operon Liver/cytology Mice Mice, Inbred C57BL Models, Genetic Nuclear Respiratory Factor 1 Nuclear Respiratory Factors Oxidation-Reduction Oxidative Stress Protein Isoforms Reactive Oxygen Species Recombinant Fusion Proteins/metabolism Reverse Transcriptase Polymerase Chain Reaction Stem Cells/cytology Tissue Distribution Trans-Activators/metabolism,physiology Tumor Necrosis Factor-alpha/metabolism
Chemicals
Antioxidants DNA-Binding Proteins Nrf1 protein, mouse Nuclear Respiratory Factor 1 Nuclear Respiratory Factors Protein Isoforms Reactive Oxygen Species Recombinant Fusion Proteins Trans-Activators Tumor Necrosis Factor-alpha Casp3 protein, mouse Caspase 3 Caspases Glutathione
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Chen Linyun
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California 94143, USA.
Kwong Mandy
Lu Ronghua
Ginzinger David
Lee Candy
Leung Laura
Chan Jefferson Y
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.13.4673-4686.2003
Published
2003-07-00
Pages
4673-86
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC164851
Subset
IM
Grants
NIDDK NIH HHS · DK02603 · United States
NIDDK NIH HHS · DK063757 · United States
External Links
PubMed source DOI: 10.1128/MCB.23.13.4673-4686.2003 PMC Full Text View journal details
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