The University of Connecticut Health Center, Department of Surgery, Cardiovascular Research Center, Farmington, Connecticut, United States; ahsan@uchc.edu.
In nonalcoholic fatty liver disease, oxidative stress is believed to play a crucial role as a second-hit for the progression of simple steatosis to steatohepatitis. Thioredoxin (TRX) is a potent antioxidant molecule that exerts anti-apoptotic and anti-inflammatory functions. TRX-binding protein-2 (TBP-2) is an endogenous negative regulator of TRX. Deficiency of TBP-2 in mice causes hyperlipidemia, hepatic steatosis, hypoglycemia and bleeding tendency, resembling Reye-syndrome in a fasting/glucose-deficient state. The aim of this study was to investigate the role of TBP-2 in the development of nonalcoholic steatohepatitis (NASH). TBP-2-deficient (TBP-2-/-) and wild type (WT) mice were fed either a normal or methionine-choline-deficient (MCD) diet for up to 10 weeks. Compared with WT mice, TBP-2-/- mice showed severe simple steatosis rather than steatohepatitis. However, oxidative stress determined by lipid peroxidation and DNA damage, neutrophil infiltration and hepatic fibrosis were attenuated in TBP-2-/- mice. PCR analysis showed the expressions of fibrosis-inducing and inflammatory-cytokine-related genes were less in TBP-2-/- mice. Moreover, leptin, SREBP1c, PPAR and adipogenesis-lipogenesis-related genes were upregulated in TBP-2-/- mice. These results strongly suggested that TBP-2 might be involved in pathogenesis of NASH in WT mice and inhibitors of TBP-2 could be useful in the prevention or treatment of NASH.