title: Prolyl oligopeptidase attenuates hepatic stellate cell activation through induction of Smad7 and PPAR-γ.
abstract: Prolyl oligopeptidase (POP) is a serine endopeptidase widely distributedin vivowith high activity in the liver. However, its biological functions in the liver have remained largely elusive. A previous study by our group has shown that POP producedN-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) and thereby exerted an anti-fibrogenic effect on hepatic stellate cells (HSCs)in vitro. It was therefore hypothesized that POP may affect the activation state of HSCs and has an important role in liver fibrosis. The HSC-T6 immortalized rat liver stellate cell line was treated with the POP inhibitor S17092 or transfected with recombinant lentivirus to overexpress POP. Cell proliferation and apoptosis were determined using a Cell Counting Kit-8 and flow cytometry, respectively. The activation status of HSCs was determined by examination of the expression of α-smooth muscle actin (α-SMA), collagen I, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor (TGF)-β-Smad signaling and peroxisome proliferator activated receptor-γ (PPAR-γ). Inhibition by S17092 decreased, whereas lentiviral expression increased the activity of POP and cell proliferation, while neither of the treatments affected cell apoptosis. Of note, S17092 significantly increased, whereas POP overexpression decreased the expression of α-SMA and MCP-1 without affecting the expression of collagen I and TGF-β1. Furthermore, S17092 caused a reduction, whereas POP overexpression caused an upregulation of Smad7 protein and PPAR-γ, but not phosphorylated-Smad2/3 expression. In conclusion, POP attenuated the activation of HSCs through inhibition of TGF-β signaling and induction of PPAR-γ, which may have therapeutic potential in liver fibrosis.
authors.affiliation: Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Da
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Ling-Nan
authors.initials: LN
authors.lastname: He
authors.affiliation: Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Bing-Hang
authors.initials: BH
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830028, P.R. China.
authors.forename: Yong-Nian
authors.initials: YN
authors.lastname: Ding
authors.affiliation: Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Yuan-Wen
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. China.
authors.forename: Jian-Gao
authors.initials: JG
authors.lastname: Fan
keywords: hepatic stellate cells; peroxisome proliferator activated receptor-γ; prolyl oligopeptidase; transforming growth factor-β-Smad signaling