Cytoprotective Nrf2 pathway is induced in chronically txnrd 1-deficient hepatocytes

Metabolically active cells require robust mechanisms to combat oxidative stress. The cytoplasmic thioredoxin reductase/thioredoxin (Txnrd1/Txn1) system maintains reduced protein dithiols and provides electrons to some cellular reductases, including peroxiredoxins. Here we generated mice in which the...

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Bibliographic Details
Published in:	PloS one 2009-07, Vol.4 (7), p.e6158-e6158
Main Authors:	Suvorova, Elena S, Lucas, Olivier, Weisend, Carla M, Rollins, Maryclare F, Merrill, Gary F, Capecchi, Mario R, Schmidt, Edward E
Format:	Article
Language:	eng
Subjects:	Adapter proteins Adults Animals Antioxidants Binding sites Biochemistry Biochemistry/Chemical Biology of the Cell Biochemistry/Transcription and Translation Biosynthesis Cell Biology Cells, Cultured Chromatin Chromatin Immunoprecipitation Clonal deletion Electrons Endoplasmic reticulum Enzymes Fibroblasts Gastroenterology and Hepatology/Hepatology Gene expression Gene Expression Profiling Genetic transcription Hepatocytes Hepatocytes - metabolism Histology Homeostasis Hybridization Immunohistochemistry Immunoprecipitation Liver Messenger RNA Metabolism Mice Molecular Biology Molecular Biology/Transcription Initiation and Activation NF-E2-Related Factor 2 - metabolism NRF2 protein Oxidation Oxidation-Reduction Oxidative stress Piaractus mesopotamicus Promoters Reductase Reductases Regulatory sequences RNA, Messenger - genetics Rodents Thioredoxin Thioredoxin Reductase 1 - genetics Thioredoxin Reductase 1 - physiology Transcription factors
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Summary:	Metabolically active cells require robust mechanisms to combat oxidative stress. The cytoplasmic thioredoxin reductase/thioredoxin (Txnrd1/Txn1) system maintains reduced protein dithiols and provides electrons to some cellular reductases, including peroxiredoxins. Here we generated mice in which the txnrd1 gene, encoding Txnrd1, was specifically disrupted in all parenchymal hepatocytes. Txnrd1-deficient livers exhibited a transcriptome response in which 56 mRNAs were induced and 12 were repressed. Based on the global hybridization profile, this represented only 0.3% of the liver transcriptome. Since most liver mRNAs were unaffected, compensatory responses were evidently effective. Nuclear pre-mRNA levels indicated the response was transcriptional. Twenty-one of the induced genes contained known antioxidant response elements (AREs), which are binding sites for the oxidative and chemical stress-induced transcription factor Nrf2. Txnrd1-deficient livers showed increased accumulation of nuclear Nrf2 protein and chromatin immunoprecipitation on the endogenous nqo1 and aox1 promoters in fibroblasts indicated that Txnrd1 ablation triggered in vivo assembly of Nrf2 on each. Chronic deletion of Txnrd1 results in induction of the Nrf2 pathway, which contributes to an effective compensatory response.
ISSN:	1932-6203 1932-6203