Accepted manuscript
A Txnrd1-dependent metabolic switch alters hepatic lipogenesis, glycogen storage, and detoxification
Free radical biology & medicine, Vol.63, pp.369-380
10/2013
Handle:
https://hdl.handle.net/2376/113042
PMCID: PMC3827783
PMID: 23743293
Abstract
Besides helping to maintain a reducing intracellular environment, the thioredoxin (Trx) system impacts bioenergetics and drug metabolism. We show that hepatocyte-specific disruption of Txnrd1, encoding Trx reductase-1 (TrxR1), causes a metabolic switch in which lipogenic genes are repressed and periportal hepatocytes become engorged with glycogen. These livers also overexpress machinery for biosynthesis of glutathione and conversion of glycogen into UDP-glucuronate; they stockpile glutathione-S-transferases and UDP-glucuronyl-transferases; and they overexpress xenobiotic exporters. This realigned metabolic profile suggested that the mutant hepatocytes might be preconditioned to more effectively detoxify certain xenobiotic challenges. Hepatocytes convert the pro-toxin acetaminophen (APAP, paracetamol) into cytotoxic N-acetyl-p-benzoquinone imine (NAPQI). APAP defenses include glucuronidation of APAP or glutathionylation of NAPQI, allowing removal by xenobiotic exporters. We found that NAPQI directly inactivates TrxR1, yet Txnrd1-null livers were resistant to APAP-induced hepatotoxicity. Txnrd1-null livers did not have more effective gene expression responses to APAP challenge; however, their constitutive metabolic state supported more robust GSH biosynthesis, glutathionylation, and glucuronidation systems. Following APAP challenge, this effectively sustained the GSH system and attenuated damage.
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- Title
- A Txnrd1-dependent metabolic switch alters hepatic lipogenesis, glycogen storage, and detoxification
- Creators
- Sonya V Iverson - Department of Immunology and Infectious Disease, Montana State University, Bozeman, MT 59718, USASofi Eriksson - Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenJianqiang Xu - Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenJustin R Prigge - Department of Immunology and Infectious Disease, Montana State University, Bozeman, MT 59718, USAEmily A Talago - Department of Immunology and Infectious Disease, Montana State University, Bozeman, MT 59718, USATesia A Meade - Department of Immunology and Infectious Disease, Montana State University, Bozeman, MT 59718, USAErin S Meade - Department of Immunology and Infectious Disease, Montana State University, Bozeman, MT 59718, USAMario R Capecchi - HHMI, University of Utah, Salt Lake City, UT, USAElias S.J Arnér - Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenEdward E Schmidt - Department of Immunology and Infectious Disease, Montana State University, Bozeman, MT 59718, USA
- Publication Details
- Free radical biology & medicine, Vol.63, pp.369-380
- Academic Unit
- Biological Sciences, School of
- Publisher
- Elsevier Inc
- Identifiers
- 99900547735501842
- Language
- English
- Resource Type
- Accepted manuscript