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

// Seon Myeong Lee 1, * , Debra Dorotea 1, * , Inji Jung 1 , Tetsuo Nakabayashi 2 , Toshio Miyata 2 and Hunjoo Ha 1 1 Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea 2 United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan * These authors contributed equally to this work Correspondence to: Hunjoo Ha, email: hha@ewha.ac.kr Keywords: plasminogen activator inhibitor 1, non-alcoholic fatty liver disease, high-fat diet, insulin resistance, organelle biogenesis Received: April 11, 2017 Accepted: September 03, 2017 Published: September 21, 2017 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.