title: Sodium valproate blocks the transforming growth factor (TGF)-β1 autocrine             loop and attenuates the TGF-β1-induced collagen synthesis in a human hepatic stellate             cell line.
abstract: Histone acetylation and deacetylation have been thought to be related to             gene expression, and there are many reports indicating that histone deacetylase             inhibitors (HDACis) exert antifibrogenic effects in several organs. In injured             livers, hepatic stellate cells (HSCs) are activated in response to profibrogenic             mediators and produce large amounts of extracellular matrix. In particular, transforming             growth factor-β1 (TGF-β1) is considered as a key factor in accelerating hepatic             fibrosis because it is released from activated HSCs and further stimulates them.             The present study aimed to clarify whether sodium valproate (VPA) has suppressive             effects on cultured human HSCs (LI90). We showed that treatment with VPA had no             significantly suppressive effect on cell proliferation at a concentration of 1 mM,             which corresponded approximately to the serum concentration obtained by the administration             of a clinical dose. However, VPA prevented the morphological changes characteristic             for activation and inhibited the expression of collagen type 1 α1 (COL1A1) and             TGF-β1 in activated LI90 cells at the mRNA and protein levels. Our results support             the hypothesis that VPA exerts antifibrogenic activity with little cytotoxicity             at 1 mM, and HDACis are expected to be used in clinical practice for the treatment             of fibrotic diseases.
authors.affiliation: Department of Gastroenterological Surgery, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan. w10423@hotmail.co.jp
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Tajima
authors.forename: Hayashi
authors.initials: H
authors.lastname: Hironori
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Nakagawara
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ohnishi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takamura
authors.forename: Itasu
authors.initials: I
authors.lastname: Ninomiya
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Sachio
authors.initials: S
authors.lastname: Fushida
authors.forename: Takashi
authors.initials: T
authors.lastname: Tani
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujimura
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ota
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Wakayama
authors.forename: Shoichi
authors.initials: S
authors.lastname: Iseki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Harada
mesh_terms: D019898:Autocrine Communication / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D024042:Collagen Type I / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D060888:Real-Time Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D024042:Collagen Type I; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D014635:Valproic Acid