TY - JOUR AB - An orally bioavailable small molecule inhibitor of plasminogen activator inhibitor‑1 (PAI‑1) is currently being clinically assessed as a novel antithrombotic agent. Although PAI‑1 is known to serve a key role in the pathogenesis of metabolic syndrome (MetS) including nonalcoholic steatohepatitis (NASH), the pharmacological action of an oral PAI‑1 inhibitor against the development of MetS‑related liver fibrosis remains unclear. The current study was designed to explicate the effect of TM5275, an oral PAI‑1 inhibitor, on MetS‑related hepatic fibrogenesis. The in vivo antifibrotic effect of orally administered TM5275 was investigated in two different rat MetS models. Fischer 344 rats received a choline‑deficient L‑amino‑acid‑defined diet for 12 weeks to induce steatohepatitis with development of severe hepatic fibrosis. Otsuka Long‑Evans Tokushima Fatty rats, used to model congenital diabetes, underwent intraperitoneal injection of porcine serum for 6 weeks to induce hepatic fibrosis under diabetic conditions. In each experimental model, TM5275 markedly ameliorated the development of hepatic fibrosis and suppressed the proliferation of activated hepatic stellate cells (HSCs). Additionally, the hepatic production of tumor growth factor (TGF)‑β1 and total collagen was suppressed. In vitro assays revealed that TGF‑β1 stimulated the upregulation of Serpine1 mRNA expression, which was inhibited by TM5275 treatment in cultured HSC‑T6 cells, a rat HSC cell line. Furthermore, TM5275 substantially attenuated the TGF‑β1‑stimulated proliferative and fibrogenic activity of HSCs by inhibiting AKT phosphorylation. Collectively, TM5275 demonstrated an antifibrotic effect on liver fibrosis in different rat MetS models, suppressing TGF‑β1‑induced HSC proliferation and collagen synthesis. Thus, PAI‑1 inhibitors may serve as effective future therapeutic agents against NASH‑based hepatic fibrosis. AD - Department of Gastroenterology, Nara Medical University, Kashihara, Nara 634‑8522, Japan United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980‑8575, Japan AU - Noguchi,Ryuichi AU - Kaji,Kosuke AU - Namisaki,Tadashi AU - Moriya,Kei AU - Kawaratani,Hideto AU - Kitade,Mitsuteru AU - Takaya,Hiroaki AU - Aihara,Yosuke AU - Douhara,Akitoshi AU - Asada,Kiyoshi AU - Nishimura,Norihisa AU - Miyata,Toshio AU - Yoshiji,Hitoshi DA - 2020/10/01 DO - 10.3892/mmr.2020.11360 EP - 2956 IS - 4 JO - Mol Med Rep KW - plasminogen activator inhibitor‑1 nonalcoholic steatohepatitis liver fibrosis hepatic stellate cell transforming growth factor‑β PY - 2020 SN - 1791-2997 1791-3004 SP - 2948 ST - Novel oral plasminogen activator inhibitor‑1 inhibitor TM5275 attenuates hepatic fibrosis under metabolic syndrome via suppression of activated hepatic stellate cells in rats T2 - Molecular Medicine Reports TI - Novel oral plasminogen activator inhibitor‑1 inhibitor TM5275 attenuates hepatic fibrosis under metabolic syndrome via suppression of activated hepatic stellate cells in rats UR - https://doi.org/10.3892/mmr.2020.11360 VL - 22 ER -