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

Title
TM5441, a plasminogen activator inhibitor-1 inhibitor, protects against high fat diet-induced non-alcoholic fatty liver disease
Authors
Lee, Seon MyeongDorotea, DebraJung, InjiNakabayashi, TetsuoMiyata, ToshioHa, Hunjoo
Ewha Authors
하헌주
SCOPUS Author ID
하헌주scopus
Issue Date
2017
Journal Title
ONCOTARGET
ISSN
1949-2553JCR Link
Citation
vol. 8, no. 52, pp. 89746 - 89760
Keywords
plasminogen activator inhibitor 1non-alcoholic fatty liver diseasehigh-fat dietinsulin resistanceorganelle biogenesis
Publisher
IMPACT JOURNALS LLC
Indexed
SCIE; SCOPUS WOS
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-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.
DOI
10.18632/oncotarget.21120
Appears in Collections:
약학대학 > 약학과 > Journal papers
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