title: Histone deacetylase 9 plays a role in the antifibrogenic effect of astaxanthin in hepatic stellate cells.
abstract: Activation of hepatic stellate cells (HSCs) is critical for liver fibrosis development. Previously, we showed that astaxanthin (ASTX), a xanthophyll carotenoid, has antifibrogenic effects in LX-2 cells, a human HSC cell line. We sought to determine the effect of ASTX on HSC activation, and to identify molecular mediators that are critically involved in the processes. ASTX prevented the activation of mouse primary HSCs, as evidenced by attenuated induction of procollagen type I α1. In human primary HSCs, ASTX also inhibited transforming growth factor β1 (TGFβ1)-induced fibrogenic gene expression. Among 11 classical histone deacetylases (HDACs), difference in HDAC9 mRNA levels between quiescent and activated HSCs was most evident while ASTX significantly decreased the expression of HDAC9 and its transcriptional regulator myocyte enhancer factor 2 (MEF2). ASTX decreased HDAC9 protein as well. In the activated HSCs, ASTX significantly reduced mRNA of HDAC9 and MEF2. Human primary biliary cirrhosis livers showed significantly higher HDAC9 mRNA and protein levels than normal livers, and other liver pathologies also exhibited induced HDAC9 expression. HDAC9 knockdown in LX-2 cells decreased TGFβ1-induced fibrogenic gene expression. In conclusion, ASTX inhibits HSC activation and facilitates HSC inactivation, which is attributable to its inhibitory action on HDAC9 expression.
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Minkyung
authors.initials: M
authors.lastname: Bae
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Young-Ki
authors.initials: YK
authors.lastname: Park
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Yoojin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Tho X
authors.initials: TX
authors.lastname: Pham
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Swetha
authors.initials: S
authors.lastname: Rudraiah
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: José
authors.initials: J
authors.lastname: Manautou
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Sung I
authors.initials: SI
authors.lastname: Koo
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA. Electronic address: ji-young.lee@uconn.edu.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Lee
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008107:Liver Diseases / Q000201:enzymology* / Q000473:pathology; D064326:MEF2 Transcription Factors / Q000235:genetics; D008810:Mice, Inbred C57BL; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D024341:Xanthophylls / Q000494:pharmacology
chemical_list: D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D012097:Repressor Proteins; D053773:Transforming Growth Factor beta1; D024341:Xanthophylls; C005948:astaxanthine; C486544:HDAC9 protein, human; C486545:Hdac9 protein, mouse; D006655:Histone Deacetylases
keywords: Astaxanthin; Carotenoids; HDAC9; Hepatic stellate cells; Histone deacetylases; Liver fibrosis