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Hepatocyte Hyperpro...
Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase
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Prigge, Justin R. (author)
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- Coppo, Lucia (author)
- Karolinska Institutet
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- Martin, Sebastin S. (author)
- Karolinska Institutet
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Ogata, Fernando (author)
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Miller, Colin G. (author)
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Bruschwein, Michael D. (author)
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Orlicky, David J. (author)
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Shearn, Colin T. (author)
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Kundert, Jean A. (author)
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Lytchier, Julia (author)
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Herr, Alix E. (author)
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- Mattsson, Åse (author)
- Karolinska Institutet
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Taylor, Matthew P. (author)
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- Gustafsson, Tomas N. (author)
- Umeå universitet,Klinisk bakteriologi,Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden,Sunderby Research Unit
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- Arnér, Elias S. J. (author)
- Karolinska Institutet
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- Holmgren, Arne (author)
- Karolinska Institutet
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Schmidt, Edward E. (author)
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(creator_code:org_t)
- Cell Press, 2017
- 2017
- English.
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In: Cell Reports. - : Cell Press. - 2211-1247. ; 19:13, s. 2771-2781
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https://umu.diva-por... (primary) (Raw object)
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Abstract
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- Energetic nutrients are oxidized to sustain high intracellular NADPH/NADP(+) ratios. NADPH-dependent reduction of thioredoxin-1 (Trx1) disulfide and glutathione disulfide by thioredoxin reductase-1 (TrxR1) and glutathione reductase (Gsr), respectively, fuels antioxidant systems and deoxyribonucleotide synthesis. Mouse livers lacking both TrxR1 and Gsr sustain these essential activities using an NADPH-independent methionine-consuming pathway; however, it remains unclear how this reducing power is distributed. Here, we show that liver-specific co-disruption of the genes encoding Trx1, TrxR1, and Gsr (triplenull) causes dramatic hepatocyte hyperproliferation. Thus, even in the absence of Trx1, methionine-fueled glutathione production supports hepatocyte S phase deoxyribonucleotide production. Also, Trx1 in the absence of TrxR1 provides a survival advantage to cells under hyperglycemic stress, suggesting that glutathione, likely via glutaredoxins, can reduce Trx1 disulfide in vivo. In triple-null livers like in many cancers, deoxyribonucleotide synthesis places a critical yet relatively low-volume demand on these reductase systems, thereby favoring high hepatocyte turnover over sustained hepatocyte integrity.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Prigge, Justin R ...
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Coppo, Lucia
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Martin, Sebastin ...
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Ogata, Fernando
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Miller, Colin G.
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Bruschwein, Mich ...
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show more...
-
Orlicky, David J ...
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Shearn, Colin T.
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Kundert, Jean A.
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Lytchier, Julia
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Herr, Alix E.
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Mattsson, Åse
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Taylor, Matthew ...
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Gustafsson, Toma ...
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Arnér, Elias S. ...
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Holmgren, Arne
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Schmidt, Edward ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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Cell Reports
- By the university
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Umeå University
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Karolinska Institutet