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.