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• W2893769734 abstract "Plasminogen activator inhibitor‐1 (PAI‐1) is a pro‐fibrotic protein that is increasingly implicated in the pathogenesis of nonalcoholic steatohepatitis (NASH). We determined the effect of genetic deletion and pharmacologic inhibition of PAI‐1 on the development of NASH‐related fibrosis in mice. We find that PAI‐1 regulates hepatic lipid accumulation but does not promote the inflammatory or fibrotic responses that characterize NASH progression. Plasminogen activator inhibitor 1 (PAI‐1), an essential regulator of fibrinolysis, is increasingly implicated in the pathogenesis of metabolic disorders, such as obesity and nonalcoholic fatty liver disease (NAFLD). Pharmacologic inhibition of PAI‐1 is emerging as a highly promising therapeutic strategy for obesity and its sequelae. Given the well‐established profibrotic function of PAI‐1, we considered whether PAI‐1 may serve as a target for antifibrotic therapy in nonalcoholic steatohepatitis (NASH). We therefore determined the effect of genetic Pai‐1 deletion and pharmacologic PAI‐1 inhibition on the development of NASH‐related fibrosis in mice. Pai‐1 knockout (Pai‐1–/–) and wild‐type control (Pai‐1+/+) mice were fed a high‐fat/high‐cholesterol high‐sugar (HFHS) diet or a methionine‐ and choline‐deficient (MCD) diet to induce steatohepatitis with fibrosis. PAI‐1 was pharmacologically inhibited using the small molecule inhibitor TM5441 in wild‐type C57BL/6 mice fed an HFHS or MCD diet. Either genetic deletion of Pai‐1 or pharmacologic inhibition of PAI‐1 attenuated MCD diet‐induced hepatic steatosis but did not prevent hepatic inflammation or fibrosis. Targeted inhibition of PAI‐1 conferred transient protection from HFHS diet‐induced obesity and hepatic steatosis, an effect that was lost with prolonged exposure to the obesigenic diet. Neither genetic deletion of Pai‐1 nor pharmacologic inhibition of PAI‐1 prevented HFHS diet‐induced hepatic inflammation or fibrosis. Conclusion:Pai‐1 regulates hepatic lipid accumulation but does not promote NASH progression. The PAI‐1 inhibitor TM5441 effectively attenuates diet‐induced obesity and hepatic steatosis but does not prevent NASH‐related fibrosis in mice." @default.
• W2893769734 created "2018-10-05" @default.
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• W2893769734 date "2018-09-26" @default.
• W2893769734 modified "2023-09-29" @default.
• W2893769734 title "Inhibition of Plasminogen Activator Inhibitor 1 Attenuates Hepatic Steatosis but Does Not Prevent Progressive Nonalcoholic Steatohepatitis in Mice" @default.
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• W2893769734 doi "https://doi.org/10.1002/hep4.1259" @default.
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