OR22-6 Reversal Of Diet Induced Metabolic Syndrome In Mice With An Orally Active Small Molecule Inhibitor Of PAI-1

Abstract

Plasminogen activator inhibitor 1 (PAI-1) is a member of the serpin family of proteases that inhibits tissue-type plasminogen activator and urokinase. Elevated levels of plasma PAI-1 are one of the hallmarks of obesity and are predictably elevated in patients with the metabolic syndrome and type 2 diabetes mellitus. Beyond these correlative relationships, increased PAI-1 levels are a predictor of, and a potential contributor to the development of obesity and diabetes. In experimental studies, mice lacking PAI-1 are resistant to weight gain and glucose intolerance when fed a high fat diet. We recently demonstrated that humans that carry a heterozygous loss-of-function mutation in the gene that codes for PAI-1 (SERPINE1) have lower fasting insulin levels and are protected from the development of diabetes compared with unaffected individuals in the same kindred. In this study, we tested the effects of the novel PAI-1 inhibitor TM5614 in reversing diet-induced obesity and glucose intolerance. Mice were fed a fast food diet for 4 months and treated with TM5614 for 10 days at the conclusion of the study period. After 1 week of treatment, the mice exhibited improvement in several metabolic measurements, including fasting glucose (from 131.2 to 92.7 mg/dL, p<0.0001), fasting plasma insulin (from 0.507 to 0.3722 ng/mL, p=0.0278) and fasting plasma LDL (from 165.1 to 118 mg/dL, p<0.0296). Mice treated with TM5614also exhibited a remarkable reduction in liver steatosis. In order the potentially identify mechanisms to explain these finding, RNA-seq of liver tissue was performed on hepatic tissue from mice treated with TM5614. The two most statistically significant changes were seen in PCSK9 (log2 fold change = -2.8 p = 3.97X10-36) and FGF21 (log2 fold change = 2.5, p = 1.03X10-31) These data suggest that suggest that PAI-1 is directly involved in the pathogenesis of not only T2DM, but also in nonalcoholic fatty liver disease and that selective inhibitors may be of benefit in the prevention and treatment of obesity and obesity-related disorders, including NASH.