Research Article Details
| Article ID: | A35753 |
| PMID: | 19764881 |
| Source: | Antioxid Redox Signal |
| Title: | Thioredoxin-binding protein-2 deficiency enhances methionine-choline deficient diet-induced hepatic steatosis but inhibits steatohepatitis in mice. |
| Abstract: | 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. |
| DOI: | 10.1089/ars.2009.2385 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S03 | Anti-fibrosis | fibrosis | Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant | Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 | Details |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| S07 | Anti-lipogenesis | de novo lipogenesis; de novo lipogenesis; DNL; anti-lipogenic mechanisms; adipogenesis; anti-obesity | stearoyl-CoA desaturase 1 (SCD-1); Acetyl-coenzyme carboxylase; acyl-CoA carboxylase inhibitor (ACC inhibitor); stearoyl Coenzyme A desaturase inhibitor (SCD inhibitor); THR-beta selective agonist; DGAT2 inhibitor; FASN inhibitor | Aramchol; Firsocostat (GS-0976); VK-2809; ION 224 | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T08 | Tumor necrosis factor | TNF | inhibitor | Cytokine | P01375 | TNFA_HUMAN | Details |
| T10 | Caspase-1 | CASP1 | inhibitor | Enzyme | P29466 | CASP1_HUMAN | Details |
| T20 | Fatty acid synthase | FASN | inhibitor | Enzyme | P49327 | FAS_HUMAN | Details |
| T05 | Peroxisome proliferator-activated receptor gamma | PPARG | agonist | Nuclear hormone receptor | P37231 | PPARG_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class |
|---|