title: Vitamin A and insulin are required for the maintenance of hepatic stellate cell quiescence.
abstract: Transdifferentiation of vitamin A-storing hepatic stellate cells (HSCs) to vitamin A-depleted myofibroblastic cells leads to liver fibrosis. Vitamin A regulates lipid accumulation and gene transcription, suggesting that vitamin A is involved in the maintenance of HSC quiescence under a physiological condition. However, the precise mechanism remains elusive because there is no appropriate in vitro culture system for quiescent HSCs. Here, we show that treatment of quiescent HSCs with vitamin A partially maintained the accumulation of lipid droplets and expression of quiescent HSC markers (glial fibrillary acidic protein, peroxisome proliferator-activator receptor-γ and CCAAT/enhancer-binding protein-α) and also the expression of myofibroblastic markers (α-smooth muscle actin, heat shock protein 47 and collagen type I). On the other hand, combined treatment with vitamin A and insulin sustained the characteristic of HSC quiescence and completely suppressed the expression of myofibroblastic markers through activation of the JAK2/STAT5 signaling pathway and increased expression of sterol regulatory element binding protein-1. These treated HSCs transdifferentiated to myofibroblastic cells under a culture condition with fetal bovine serum. The results suggest an important role of vitamin A and insulin in the maintenance of HSC quiescence under a physiological condition.
authors.affiliation: Department of Molecular Therapeutics, Center for Food & Medical Innovation, Institute for the Promotion of Business-Regional Collaboration, Hokkaido University, West-11, North-21, Kita-ku, Sapporo 001-0021, Hokkaido, Japan. Electronic address: ayoneda@fmi.hokudai.ac.jp.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yoneda
authors.affiliation: Department of Molecular Therapeutics, Center for Food & Medical Innovation, Institute for the Promotion of Business-Regional Collaboration, Hokkaido University, West-11, North-21, Kita-ku, Sapporo 001-0021, Hokkaido, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakai-Sawada
authors.affiliation: Department of Molecular Target Exploration, School of Medicine, Sapporo Medical University, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Niitsu
authors.affiliation: Department of Molecular Therapeutics, Center for Food & Medical Innovation, Institute for the Promotion of Business-Regional Collaboration, Hokkaido University, West-11, North-21, Kita-ku, Sapporo 001-0021, Hokkaido, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Tamura
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000166:cytology* / Q000187:drug effects*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014801:Vitamin A / Q000494:pharmacology*
chemical_list: D007328:Insulin; D014801:Vitamin A
keywords: HSC quiescence; Hepatic stellate cells; Insulin; Vitamin A