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Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase
- Prigge, Justin R. (author)
-
- Coppo, Lucia (author)
- Karolinska Institutet
-
- Martin, Sebastin S. (author)
- Karolinska Institutet
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- Ogata, Fernando (author)
- Miller, Colin G. (author)
- Bruschwein, Michael D. (author)
- Orlicky, David J. (author)
- Shearn, Colin T. (author)
- Kundert, Jean A. (author)
- Lytchier, Julia (author)
- Herr, Alix E. (author)
- Taylor, Matthew P. (author)
- Schmidt, Edward E. (author)
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- (creator_code:org_t)
- Cell Press, 2017
- 2017
- English.
- In: Cell Reports. - : Cell Press. - 2211-1247. ; 19:13, s. 2771-2781
- Journal article (peer-reviewed)
Abstract
Subject headings
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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)
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