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

Elena S Suvorova; Olivier Lucas; Carla M Weisend; Maryclare F Rollins; Gary F Merrill; Mario R Capecchi; Edward E Schmidt

doi:10.1371/journal.pone.0006158

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

Journal article

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

Elena S Suvorova, Olivier Lucas, Carla M Weisend, Maryclare F Rollins, Gary F Merrill, Mario R Capecchi and Edward E Schmidt

PloS one, Vol.4(7), pp.e6158-e6158

07/07/2009

DOI: https://doi.org/10.1371/journal.pone.0006158

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https://hdl.handle.net/2376/113589

PMCID: PMC2703566

PMID: 19584930

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Abstract

Immunohistochemistry

Animals

Chromatin Immunoprecipitation

Oxidation-Reduction

Thioredoxin Reductase 1 - physiology

NF-E2-Related Factor 2 - metabolism

RNA, Messenger - genetics

Cells, Cultured

Gene Expression Profiling

Mice

Thioredoxin Reductase 1 - genetics

Hepatocytes - metabolism

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.

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Title: Cytoprotective Nrf2 pathway is induced in chronically txnrd 1-deficient hepatocytes
Creators: Elena S Suvorova - Veterinary Molecular Biology, Montana State University, Bozeman, Montana, USA
Olivier Lucas
Carla M Weisend
Maryclare F Rollins
Gary F Merrill
Mario R Capecchi
Edward E Schmidt
Publication Details: PloS one, Vol.4(7), pp.e6158-e6158
Academic Unit: UNKNOWN
Publisher: United States
Grant note: 2P20RR020285 / NCRR NIH HHS
Identifiers: 99900548173401842
Language: English
Resource Type: Journal article