All-trans retinoic acid ameliorates hepatic stellate cell activation via suppression of thioredoxin interacting protein expression.
Activation of hepatic stellate cells (HSCs) is the effector factor of hepatic fibrosis and hepatocellular carcinoma (HCC) development. Accumulating evidence suggests that retinoic acids (RAs), derivatives of vitamin A, contribute to prevention of liver fibrosis and carcinogenesis, however, regulatory mechanisms of RAs still remain exclusive. To elucidate RA signaling pathway, we previously performed a genome-wide screening of RA-responsive genes by in silico analysis of RA-response elements, and identified 26 RA-responsive genes. We found that thioredoxin interacting protein (TXNIP), which inhibits antioxidant activity of thioredoxin (TRX), was downregulated by all-trans retinoic acid (ATRA). In the present study, we demonstrate that ATRA ameliorates activation of HSCs through TXNIP suppression. HSC activation was attenuated by TXNIP downregulation, whereas potentiated by TXNIP upregulation, indicating that TXNIP plays a crucial role in activation of HSCs. Notably, we showed that TXNIP-mediated HSC activation was suppressed by antioxidant N-acetylcysteine. In addition, ATRA treatment or downregulation of TXNIP clearly declined oxidative stress levels in activated HSCs. These data suggest that ATRA plays a key role in inhibition of HSC activation via suppressing TXNIP expression, which reduces oxidative stress levels.
Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan.
Hiroki
H
Shimizu
Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan.
Toshiaki
http://orcid.org/0000-0002-9126-9333
T
Tsubota
Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan.
Keita
K
Kanki
Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan.
Goshi
G
Shiota
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014802:Vitamin A Deficiency / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D000975:Antioxidants; D002352:Carrier Proteins; C486715:TXNIP protein, human; C445672:Txnip protein, mouse; D013879:Thioredoxins; D014212:Tretinoin
all-trans retinoic acid (ATRA); fibrosis; hepatic stellate cell (HSC); liver cancer; oxidative stress; retinoic acid; thioredoxin interacting protein (TXNIP)