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Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis
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Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis
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Journal Article
Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis
2023
Overview
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.
In this study, Oaks and Patel et al. characterize the crosstalk between the pentose phosphate pathway and mitochondrial redox homeostasis in the context of aldose reductase and transaldolase deficiency and the contribution of pentose phosphate pathway mitochondria deregulation to the progression from cirrhosis to hepatocellular carcinoma.
