TM5441, a plasminogen activator inhibitor-1 inhibitor, protects against high fat diet-induced non-alcoholic fatty liver disease
- 주제(키워드) plasminogen activator inhibitor 1 , non-alcoholic fatty liver disease , high-fat diet , insulin resistance , organelle biogenesis
- 주제(기타) Oncology; Cell Biology
- 설명문(일반) [Lee, Seon Myeong; Dorotea, Debra; Jung, Inji; Ha, Hunjoo] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Coll Pharm, Seoul, South Korea; [Nakabayashi, Tetsuo; Miyata, Toshio] Tohoku Univ, Grad Sch Med, United Ctr Adv Res & Translat Med, Sendai, Miyagi, Japan
- 등재 SCIE, SCOPUS
- 발행기관 IMPACT JOURNALS LLC
- 발행년도 2017
- URI http://www.dcollection.net/handler/ewha/000000150110
- 본문언어 영어
- Published As http://dx.doi.org/10.18632/oncotarget.21120
초록/요약
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-GSK3 beta, reduced p-JNK signaling, along with p-AMPK and PGC-1 alpha activation. Consistently, TM5441 treatment in the presence of either PAI-1 exposure or TNF-alpha 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.
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