TM5441, a plasminogen activator inhibitor-1 inhibitor, protects against high fat diet-induced non-alcoholic fatty liver disease

Abstract

Recent evidences showed that elevation of plasminogen activator inhibitor 1 (PAI-1) was responsible in mediating obesity-induced non-alcoholic fatty liver disease (NAFLD) and metabolic disorders. Here, we investigated the effect of TM5441, an oral PAI-1 inhibitor that lacks of bleeding risk, on high-fat diet (HFD)-induced NAFLD. HFD-fed C57BL/6J mice was daily treated with 20 mg/kg TM5441. To examine the preventive effect, 10-week-treatment was started along with initiation of HFD; alternatively, 4-week-treatment was started in mice with glucose intolerance in the interventional strategy. In vivo study showed that early and delayed treatment decreased hepatic steatosis. Particularly, early treatment prevented the progression of hepatic inflammation and fibrosis in HFD mice. Interestingly, both strategies abrogated hepatic insulin resistance and mitochondrial dysfunction, presented by enhanced p-Akt and p-GSK3β, reduced p-JNK signaling, along with p-AMPK and PGC-1α activation. Consistently, TM5441 treatment in the presence of either PAI-1 exposure or TNF-α stimulated-PAI-1 activity showed a restoration of mitochondrial biogenesis related genes expression on HepG2 cells. Thus, improvement of insulin sensitivity and mitochondrial function was imperative to partially explain the therapeutic effects of TM5441, a novel agent targeting HFD-induced NAFLD.

Stress granules counteract senescence by sequestration of PAI‐1

“…Since PAI‐1 is a well‐known promoter of senescence downstream of p53 , its depletion or chemical inhibition should impact the induction of senescence similarly to when primary fibroblasts are repeatedly exposed to AS. To determine the importance of PAI‐1 in this process, we used specific siRNA duplexes to knockdown PAI‐1 expression and employed the well‐established small‐molecule inhibitor of PAI‐1 TM5441 (Fig A) . Our data indicate that both PAI‐1 knockdown (Fig B) and TM5441‐mediated inhibition (Fig C) were sufficient to promote a significant decrease in the number of β‐galactosidase‐positive cells in the presence or absence of AS treatment.…”

“…Cells induced into senescence were treated with 10 μM TM5441 (Tocris Bioscience) for 24 h daily after treatment with AS .…”

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

“…Heterozygosity of a null PAI‐1 mutation in humans is associated with lower fasting insulin levels and a lower prevalence of diabetes . Furthermore, a novel small molecule inhibitor of PAI‐1, TM5441, has recently been shown to attenuate high‐fat diet‐induced obesity and hepatic steatosis in mice . Given the potential role of PAI‐1 in promoting metabolic disease combined with its established profibrotic properties, we hypothesized that PAI‐1 may serve as an ideal therapeutic target for NASH‐related fibrosis.…”

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.…”