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

Anne S. Henkel, Sadiya S. Khan, Shantel Olivares, Toshio Miyata, Douglas E. Vaughan

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)1479-1492
Number of pages14
JournalHepatology Communications
Volume2
Issue number12
DOIs
Publication statusPublished - 2018 Dec
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology

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