期刊
CELL REPORTS
卷 19, 期 13, 页码 2771-2781出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.06.019
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资金
- National Institute on Aging from the Montana Agricultural Experiment Station [AG040020, AG055022, GM110732, DK 079626]
- Swedish WennerGren Foundation
- Karolinska Institutet
- Swedish Research Council [2013-4054, 2014-2603, 2013-3529]
- Swedish Cancer Society [2015/238, 2015-961]
- Knut and Alice Wallenberg Foundation [2015/238]
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.
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