title: Fusion protein of retinol-binding protein and albumin domain III reduces liver fibrosis.
abstract: Activated hepatic stellate cells (HSCs) play a key role in liver fibrosis, and inactivating HSCs has been considered a promising therapeutic approach. We previously showed that albumin and its derivative designed for stellate cell-targeting, retinol-binding protein-albumin domain III fusion protein (referred to as R-III), inactivate cultured HSCs. Here, we investigated the mechanism of action of albumin/R-III in HSCs and examined the anti-fibrotic potential of R-III in vivo. R-III treatment and albumin expression downregulated retinoic acid (RA) signaling which was involved in HSC activation. RA receptor agonist and retinaldehyde dehydrogenase overexpression abolished the anti-fibrotic effect of R-III and albumin, respectively. R-III uptake into cultured HSCs was significantly decreased by siRNA-STRA6, and injected R-III was localized predominantly in HSCs in liver. Importantly, R-III administration reduced CCl4- and bile duct ligation-induced liver fibrosis. R-III also exhibited a preventive effect against CCl4-inducd liver fibrosis. These findings suggest that the anti-fibrotic effect of albumin/R-III is, at least in part, mediated by downregulation of RA signaling and that R-III is a good candidate as a novel anti-fibrotic drug.
authors: Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea.
authors: Hongsik
authors: H
authors: Lee
authors: Department of Anatomy, College of Medicine, Korea University, Seoul, Korea.
authors: Hyeyeun
authors: H
authors: Jeong
authors: Department of Anatomy, College of Medicine, Korea University, Seoul, Korea.
authors: Sangeun
authors: S
authors: Park
authors: Department of Anatomy, College of Medicine, Korea University, Seoul, Korea.
authors: Wonbaek
authors: W
authors: Yoo
authors: Department of Anatomy, College of Medicine, Korea University, Seoul, Korea.
authors: Soyoung
authors: S
authors: Choi
authors: Department of Physiology, College of Medicine, Korea University, Seoul, Korea.
authors: Kyungmin
authors: K
authors: Choi
authors: Department of Physiology, College of Medicine, Korea University, Seoul, Korea.
authors: Min-Goo
authors: MG
authors: Lee
authors: Department of Nephrology, College of Medicine, Korea University, Seoul, Korea.
authors: Mihwa
authors: M
authors: Lee
authors: Department of Nephrology, College of Medicine, Korea University, Seoul, Korea.
authors: DaeRyong
authors: D
authors: Cha
authors: Department of Pathology, College of Medicine, Korea University, Seoul, Korea.
authors: Young-Sik
authors: YS
authors: Kim
authors: Department of Pathology, Inha University Hospital, Incheon, Korea.
authors: Jeeyoung
authors: J
authors: Han
authors: Medical Proteomics Research Center, KRIBB, Daejeon, Korea.
authors: Wonkon
authors: W
authors: Kim
authors: Department of Anatomy, College of Medicine, Korea University, Seoul, Korea.
authors: Sun-Hwa
authors: SH
authors: Park
authors: Department of Anatomy, College of Medicine, Korea University, Seoul, Korea ohjs@korea.ac.kr.
authors: Junseo
authors: J
authors: Oh
mesh_terms: D000418:Albumins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000502:physiology; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008807:Mice, Inbred BALB C; D008853:Microscopy; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D012177:Retinol-Binding Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000378:metabolism
chemical_list: D000418:Albumins; D011993:Recombinant Fusion Proteins; D012177:Retinol-Binding Proteins; D014212:Tretinoin
keywords: albumin; anti‐fibrotic drug; fibrosis; hepatic stellate cell; retinoic acid