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

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

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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-1a activation. Consistently, TM5441 treatment in the presence of either PAI-1 exposure or TNF-a 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.

Original languageEnglish
Pages (from-to)89746-89760
Number of pages15
JournalOncotarget
Volume8
Issue number52
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
The authors acknowledge the excellent technical assistant of Jung Hwa Lee. This work was financially supported by NLRL through the National Research Foundation (NRF) of Korea (No. 2016R1A2B4006575).

Publisher Copyright:
© Lee et al.

Keywords

  • High-fat diet
  • Insulin resistance
  • Non-alcoholic fatty liver disease
  • Organelle biogenesis
  • Plasminogen activator inhibitor 1

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