Thioredoxin-binding protein-2 deficiency enhances methionine-choline deficient diet-induced hepatic steatosis but inhibits steatohepatitis in mice.
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.
Ahsan
Md Kaimul
MK
Thioredoxin Project, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto, Japan.
Okuyama
Hiroaki
H
Hoshino
Yuma
Y
Oka
Shin-Ichi
S
Masutani
Hiroshi
H
Yodoi
Junji
J
Nakamura
Hajime
H
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002796:Choline Deficiency / Q000378:metabolism*; D004032:Diet; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006505:Hepatitis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; C445672:Txnip protein, mouse; D013879:Thioredoxins; D007371:Interferon-gamma; D008715:Methionine