Potential conflict of interest: Nothing to report.
TAL deficiency, all roads lead to oxidative stress?†
Article first published online: 27 AUG 2009
Copyright © 2009 American Association for the Study of Liver Diseases
Volume 50, Issue 3, pages 979–981, September 2009
How to Cite
Hatting, M., Trautwein, C., Cubero, F. J. (2009), TAL deficiency, all roads lead to oxidative stress?. Hepatology, 50: 979–981. doi: 10.1002/hep.23227
- Issue published online: 27 AUG 2009
- Article first published online: 27 AUG 2009
Hanczko R, Fernandez DR, Doherty E, Qian Y, Vas G, Niland B, et al. Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine. J Clin Invest 2009;6:1546–1557. (Reprinted with permission.)
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 β-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. (HEPATOLOGY 2009;50:)
In the late 1940s, Dr. Horecker1 made history in Building 3 at the National Institutes of Health by describing the pentose phosphate pathway (PPP). Metabolism of glucose through the PPP fulfils two unique functions: (1) formation of ribose 5-phosphate for the synthesis of nucleotides, RNA, and DNA; and (2) production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) as a reducing agent for many biosynthetic reactions as well as an important compound for protection against oxidative damage.2, 3 The pathway (Fig. 1) comprises two separate branches: the oxidative branch which converts glucose 6-phosphate to a pentose phosphate by producing NADPH, and the nonoxidative branch which gives connection directly to the adenosine triphosphate synthesis.3 Understanding regulation of the PPP has regained interest among liver researchers after recent case reports suggest a link between transaldolase (TAL), the rate-limiting enzyme of the nonoxidative branch of the PPP, and liver failure.3–7
In humans, TAL is encoded by the TALDO1 gene located on chromosome 11.8 The three–base pair deletion in the TALDO1 gene results in the absence of 171Ser, producing the TAL deficiency.5 Although the severity of the manifestation of the disease differs dramatically, all patients show common symptoms such as hydrops fetalis, genitourinary malformations, hepatosplenomegaly, hemolytic anemia, kidney failure, and cardiomyopathy.7 The importance of human TAL deficiency was recognized because it has been associated with autoimmune diseases (multiple sclerosis and rheumatoid arthritis), cancer (leukemia, skin, lung, colon, esophagus, breast, kidney, and liver cancer), and liver cirrhosis.3, 9 The TAL null (TALDO1–/–) mice were developed in Dr. Perl's laboratory10 by homologous recombination and inactivation of the TAL locus. Mice deficient in TALDO1 develop normally, with the exception of sperm dysmotility due to lower mitochondrial membrane potential (ψm) and a destruction of the internal membrane structure in the mitochondria.3, 9 The same group has recently reported that these mice spontaneously develop hepatocellular carcinoma (HCC).10
In a move toward understanding the role of TAL in hepatocarcinogenesis and liver cirrhosis, Hanczko and coworkers10 further characterized the phenotype of TALDO1–/– mice. As expected, these mice present cirrhosis-like collagen fibers, dysplastic nodules, cellular atypia, anisonucleosis, mitosis, and increased nuclear-to-cytoplasmic ratio. Typical features such as impaired glucose tolerance, accumulation of lipid droplets, and diminished size and numbers of mitochondria indicative of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis were also observed.
Glucose metabolism through the PPP provides ribose-5 phosphate to preserve the cellular redox equilibrium, and for maintenance of glutathione (GSH) in its reduced state (Fig. 1). The authors assessed the contribution of TAL to the nonoxidative branch of the PPP. They found that TALDO1–/– mice showed reduced NADPH and GSH levels. Thus, the reductive atmosphere required for cellular integrity and protection against oxidative stress is impaired.11 The authors evaluated some of the key enzymes involved in the antioxidant defense in the cell. Superoxide dismutase, catalase, and GSH peroxidase are key enzymes involved in the antioxidant defense in the cell. The authors found an increase in the antioxidant system of TALDO1–/– mice and identified lipid peroxidation as a source of reactive oxygen species (ROS). A balance between NADPH, GSH, and ROS by the PPP enzyme TAL regulates ψm, critical in the synthesis of adenosine triphosphate and cell survival.3 The ψm and the mitochondrial mass were reduced in TALDO1–/– hepatocytes, and Fas-mediated apoptosis, associated to cell survival, was also reduced in TALDO1–/– mice.
An important factor involved in the development of HCC is the DNA damage caused by oxidative stress.12 The authors screened for markers for HCC and showed that c-Jun, alpha-fetoprotein, and aldose reductase were increased in TALDO1–/– livers. ROS can modulate signaling of the Wnt/β-catenin pathway, involved in HCC.13 They found diminished phosphorylation of β-catenin associated with diffuse accumulation in the cytosol of TALDO1–/– hepatomas and translocation of β-catenin into the nuclei of cancer cells. Having dissected the role of TAL deficiency and HCC, the authors experimentally approached the link between liver injury and the lack of the PPP enzyme. They selected acetaminophen (APAP) as the model of acute-liver injury. TALDO1–/– mice showed increased susceptibility to APAP and died of fulminant liver necrosis. Presumably, this is due to the decreased levels of GSH, the antioxidant involved in the detoxification of APAP. Regarding this, Hanczko and collaborators decided to use N-acetylcysteine (NAC), a precursor of GSH and treatment of choice for APAP-induced acute liver failure.14 The authors administered NAC which normalized both GSH and NADPH levels, ROS, ψm, mitochondrial mass, susceptibility to Fas-induced cell death, and β-catenin phosphorylation.
In summary, the article by Hanczko and colleagues is the first to establish a direct link between the metabolic basis of the TAL deficiency of the PPP in the liver, characterized by the accumulation of five-carbon sugar phosphates and by the depletion of NADPH and GSH, which underlie mitochondrial dysfunction and oxidative stress, the latter predisposing to both HCC and APAP-induced acute liver failure. Conceivably, the use of oral NAC, which has already been shown to prevent TAL deficiency–associated sperm dysmotility and GSH depletion—with further prevention of HCC and APAP-induced liver injury—could be a useful treatment in patients with metabolic liver disease.