Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.
Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1-/- and Taldo1+/- mice spontaneously developed HCC, and Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1-/- livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress. Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1-/- mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency.
Hanczko
Robert
R
Department of Medicine, College of Medicine, State University of New York, Syracuse, New York 13210, USA.
Fernandez
David R
DR
Doherty
Edward
E
Qian
Yueming
Y
Vas
Gyorgy
G
Niland
Brian
B
Telarico
Tiffany
T
Garba
Adinoyi
A
Banerjee
Sanjay
S
Middleton
Frank A
FA
Barrett
Donna
D
Barcza
Maureen
M
Banki
Katalin
K
Landas
Steve K
SK
Perl
Andras
A
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D017093:Liver Failure / Q000139:chemically induced*; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation; D014153:Transaldolase / Q000172:deficiency* / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D014408:Biomarkers, Tumor; D000509:alpha-Fetoproteins; D051176:beta Catenin; D019014:fas Receptor; D014153:Transaldolase; D048031:JNK Mitogen-Activated Protein Kinases; D000111:Acetylcysteine