Thioredoxin-binding protein-2 deficiency enhances methionine-choline deficient diet-induced hepatic steatosis but inhibits steatohepatitis in mice

Antioxid Redox Signal. 2009 Oct;11(10):2573-84. doi: 10.1089/ars.2009.2385.


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, PPARgamma, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Choline Deficiency / metabolism*
  • Diet*
  • Fatty Liver* / etiology
  • Fatty Liver* / metabolism
  • Fatty Liver* / pathology
  • Female
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Hepatitis* / etiology
  • Hepatitis* / metabolism
  • Hepatitis* / pathology
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Liver / cytology
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Methionine / deficiency*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neutrophils / cytology
  • Neutrophils / metabolism
  • Oxidative Stress
  • Thioredoxins / genetics
  • Thioredoxins / metabolism*
  • Triglycerides / blood
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism


  • Carrier Proteins
  • Interleukin-1beta
  • NF-kappa B
  • Triglycerides
  • Tumor Necrosis Factor-alpha
  • Txnip protein, mouse
  • Thioredoxins
  • Interferon-gamma
  • Methionine