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

Seon Myeong Lee,Inji Jung,Debra Dorotea,Toshio Miyata,Hunjoo Ha,Tetsuo Nakabayashi

doi:10.18632/oncotarget.21120

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.

Highlights

Non-alcoholic fatty liver disease (NAFLD) can range from simple steatosis, inflammatory steatohepatitis (NASH) with increasing severity of fibrosis, and cirrhosis [1]
We showed that compared to normal diet (ND) mice, 10-week-high-fat diet (HFD) mice had significant elevations of hepatic TG content and lipid accumulation in liver tissue which were remarkably reduced in response to TM5441 (Figure 1A, 1B)
To investigate whether HFD-induced hepatic insulin resistance might be prevented by TM5441, we measured proteins involved in insulin signaling, such as Akt, GSK3β, and c-Jun N-terminal kinase (JNK)

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) can range from simple steatosis, inflammatory steatohepatitis (NASH) with increasing severity of fibrosis, and cirrhosis [1]. NAFLD represents the most common cause of liver disease in developed countries [2, 3]. Detailed pathogenic mechanism of NAFLD progression is not yet fully understood which limits the development of therapeutic agents [4, 5]. PAI-1 is widely known as an endogenous inhibitor of plasminogen activation by tissue-type and urokinase-type plasminogen activator (t-PA and u-PA, respectively) [6]. Plasma and tissue concentration of PAI1 are extremely low on basal condition but elevated under pathological conditions. Increased PAI-1 activity has been associated with higher risk of metabolic syndromes, cardiovascular events, and tissue fibrosis [7, 8]

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Results

Conclusion