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


RESULTS
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.


CONCLUSIONS
Chronic deletion of Txnrd1 results in induction of the Nrf2 pathway, which contributes to an effective compensatory response.
Suvorova
Elena S
ES
Veterinary Molecular Biology, Montana State University, Bozeman, Montana, USA.
Lucas
Olivier
O
Weisend
Carla M
CM
Rollins
Maryclare F
MF
Merrill
Gary F
GF
Capecchi
Mario R
MR
Schmidt
Edward E
EE
D000818:Animals; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics; D054481:Thioredoxin Reductase 1 / Q000235:genetics / Q000502:physiology*
D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D054481:Thioredoxin Reductase 1; C516125:Txnrd1 protein, mouse