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

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.

Endoplasmic reticulum stress induces hepatic plasminogen activator inhibitor 1 in murine nonalcoholic steatohepatitis

“…We have previously shown that MCD diet-induced NASH is associated with marked induction OLIVARES And HEnKEL of hepatic ER stress as well as increased hepatic expression of Pai-1. 8,31 To establish whether this relationship is cause and effect, wild-type C57BL6/J mice were fed a MCD or methionine-and choline-sufficient (MCS) diet with or without the ER stress inhibitor, 4-phenylbutyric acid (4-PBA), for 14 days. Consistent with our previous observations in mice fed the MCD diet for 8 weeks, the livers of mice fed a MCD diet for 14 days showed activation of the UPR and significant induction of hepatic Pai-1 expression ( Figure 5).…”

“…In particular, UPR dysfunction has been strongly linked to human metabolic diseases such as obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD). [5][6][7][8][9][10][11][12][13] Plasminogen activator inhibitor-1 (PAI-1) is a stress-responsive gene that is in induced in response to tissue injury and serves a physiologic role in wound healing. Although best known for its function as an inhibitor of fibrinolysis, PAI-1 also regulates inflammation and fibrosis in numerous tissue types.…”

“…[10][11][12][13] In particular, PAI-1 expression is highly induced in the livers of mice and humans with nonalcoholic steatohepatitis (NASH). [7][8][9]21 Although the association between metabolic disease and induction of PAI-1 is well-established, the mechanism by which metabolic derangements induce PAI-1 is unknown. Given that induction of hepatic ER stress is a well-recognized feature of NASH, 22 we considered whether ER stress contributes to the characteristic induction of PAI-1 in NASH.…”

Association between plasminogen activator inhibitor‐1 in young adulthood and nonalcoholic fatty liver disease in midlife: CARDIA

“…For example, PAI‐1 levels have a higher correlation with liver fat content than visceral fat content 34 . In addition, prior work in murine models showing that PAI‐1‐deficient mice and wild type mice given a small molecular inhibitor of PAI‐1 were protected against diet‐induced steatosis formation 20‐22 further supports the hypothesis that PAI‐1 may be playing an important role in NAFLD pathophysiology.…”

“…Preclinical data supporting the biologic plausibility of PAI‐1 playing a causal role in the development of NAFLD include findings in a murine model exposed to a high fructose diet in which PAI‐1‐deficient mice were protected against the development of hepatic steatosis 20 . Furthermore, administration of a small molecule inhibitor of PAI‐1 attenuated high‐fat diet‐induced hepatic steatosis in two separate murine studies, 21,22 showing the potential to prevent NAFLD development with PAI‐1‐targeted therapies.…”