RNA-Sequencing of Transaldolase and Aldose Reducatase Deficiency in Mouse Liver

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 ratelimiting enzyme of the non-oxidative branch of the pentose phosphate pathway (PPP), elicits growth restriction, and predisposes to cirrhosis and HCC in mice and humans. Here, we show that mitochondrial oxidative stress and disease progression from cirrhosis to HCC and acetaminophen-induced liver necrosis are critically dependent on NADPH depletion by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and stunted growth in TAL deficiency. Both TAL and AR are confined to the cytosol, however, their inactivation distorts NADPH production and mitochondrial oxidative stress into opposite directions. Overall design: Adult mice with heterozygous deletion of transaldolase (TAL+/-) were created and fully backcrossed for >10 generations onto the C57BL/6 strain. TAL+/- and Akr1b3-deficient aldose reductase (AR) knockout (ARKO) strains were crossed to generate double-knockout (DKO) mice lacking both TAL and AR. Both TAL-deficient and DKO mice were breed as heterozygotes for the TAL locus. Wild-type (WT or TAL+/+AR+/+), TAL-deficient (TALKO or TAL-/-AR+/+), AR-deficient (ARKO or TAL+/+AR-/-), and double-knockout (DKO, or TAL-/-AR-/-) mice were matched for age and gender in each experiments. Livers were harvested from adult mice and RNA processed for RNA-Sequencing.