Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase

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.

Coppo, LuciaKarolinska Institutet (author)
Martin, Sebastin S.Karolinska Institutet (author)
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)
Mattsson, ÅseKarolinska Institutet (author)
Taylor, Matthew P. (author)
Gustafsson, Tomas N.Umeå universitet,Klinisk bakteriologi,Division of Biochemistry, Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden,Sunderby Research Unit(Swepub:umu)togu0028 (author)
Arnér, Elias S. J.Karolinska Institutet (author)
Holmgren, ArneKarolinska Institutet (author)
Schmidt, Edward E. (author)
Karolinska InstitutetKlinisk bakteriologi (creator_code:org_t)

By the author/editor: Prigge, Justin R ...; Coppo, Lucia; Martin, Sebastin ...; Ogata, Fernando; Miller, Colin G.; Bruschwein, Mich ...; show more...; Orlicky, David J ...; Shearn, Colin T.; Kundert, Jean A.; Lytchier, Julia; Herr, Alix E.; Mattsson, Åse; Taylor, Matthew ...; Gustafsson, Toma ...; Arnér, Elias S. ...; Holmgren, Arne; Schmidt, Edward ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.