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

研究成果: Article査読

13 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)89746-89760
ページ数15
ジャーナルOncotarget
8
52
DOI
出版ステータスPublished - 2017

ASJC Scopus subject areas

  • 腫瘍学

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