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Inhibition of Plasminogen Activator Inhibitor 1 Attenuates Hepatic Steatosis but Does Not Prevent Progressive Nonalcoholic Steatohepatitis in Mice. | LitMetric

AI Article Synopsis

  • PAI-1 is a key player in regulating fibrinolysis and is linked to metabolic diseases like obesity and NAFLD, making it a target for new treatments.
  • Research on mice showed that both genetic deletion and drug inhibition of PAI-1 can reduce fat accumulation in the liver but do not stop inflammation or fibrosis related to NASH.
  • The PAI-1 inhibitor TM5441 can temporarily reduce obesity and liver fat due to high-fat diets, but its effects diminish over time and it does not prevent liver fibrosis.

Article Abstract

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 deletion and pharmacologic PAI-1 inhibition on the development of NASH-related fibrosis in mice. knockout ( ) and wild-type control ( ) 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 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 nor pharmacologic inhibition of PAI-1 prevented HFHS diet-induced hepatic inflammation or fibrosis. 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287480PMC
http://dx.doi.org/10.1002/hep4.1259DOI Listing

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