TY - JOUR
T1 - Novel oral plasminogen activator inhibitor.1 inhibitor TM5275 attenuates hepatic fibrosis under metabolic syndrome via suppression of activated hepatic stellate cells in rats
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
N1 - Funding Information:
The present study was supported by Japan Society for the Promotion of Science KaKenHi (grant no. JP2646101).
PY - 2020/10
Y1 - 2020/10
N2 - 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 (NA SH), 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.E vans 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). 1 and total collagen was suppressed. In vitro assays revealed that TGF. 1 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. 1.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. 1.induced HSC proliferation and collagen synthesis. Thus, PAI. 1 inhibitors may serve as effective future therapeutic agents against NASH.based hepatic fibrosis.
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 (NA SH), 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.E vans 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). 1 and total collagen was suppressed. In vitro assays revealed that TGF. 1 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. 1.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. 1.induced HSC proliferation and collagen synthesis. Thus, PAI. 1 inhibitors may serve as effective future therapeutic agents against NASH.based hepatic fibrosis.
UR - http://www.scopus.com/inward/record.url?scp=85091060294&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85091060294&partnerID=8YFLogxK
U2 - 10.3892/mmr.2020.11360
DO - 10.3892/mmr.2020.11360
M3 - Article
C2 - 32945412
AN - SCOPUS:85091060294
VL - 22
SP - 2948
EP - 2956
JO - Molecular Medicine Reports
JF - Molecular Medicine Reports
SN - 1791-2997
IS - 4
ER -