Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.

Autor: Oaks Z; Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, USA.; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Patel A; Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, USA.; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Huang N; Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, USA.; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Choudhary G; Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, USA.; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Winans T; Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, USA.; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Faludi T; Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Krakko D; Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Duarte M; Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Lewis J; Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Beckford M; Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Blair S; Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Kelly R; Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Landas SK; Departments of Pathology, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Middleton FA; Departments of Neuroscience, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Asara JM; Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Chung SK; Faculty of Medicine, Macau University of Science and Technology, Taipa, China., Fernandez DR; Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, USA.; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Banki K; Departments of Pathology, State University of New York, Norton College of Medicine, Syracuse, NY, USA., Perl A; Departments of Medicine, State University of New York, Norton College of Medicine, Syracuse, NY, USA. perla@upstate.edu.; Departments of Biochemistry and Molecular Biology, State University of New York, Norton College of Medicine, Syracuse, NY, USA. perla@upstate.edu.; Departments of Microbiology and Immunology, State University of New York, Norton College of Medicine, Syracuse, NY, USA. perla@upstate.edu.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2023 Jan; Vol. 5 (1), pp. 41-60. Date of Electronic Publication: 2023 Jan 19.
DOI: 10.1038/s42255-022-00711-9
Abstrakt: Oxidative stress modulates carcinogenesis in the liver; however, direct evidence for metabolic control of oxidative stress during pathogenesis, particularly, of progression from cirrhosis to hepatocellular carcinoma (HCC), has been lacking. Deficiency of transaldolase (TAL), a rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway (PPP), restricts growth and predisposes to cirrhosis and HCC in mice and humans. Here, we show that mitochondrial oxidative stress and progression from cirrhosis to HCC and acetaminophen-induced liver necrosis are critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Both TAL and AR are confined to the cytosol; however, their inactivation distorts mitochondrial redox homeostasis in opposite directions. The results suggest that AR acts as a rheostat of carbon recycling and NADPH output of the PPP with broad implications for disease progression from cirrhosis to HCC.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz: