Abstract
Fasiglifam (TAK-875) a G-protein coupled receptor 40 (GPR40) agonist, significantly improves hyperglycemia without hypoglycemia and weight gain, the major side effects of conventional anti-diabetics. Unfortunately, during multi-center Phase 3 clinical trials, unexpected liver toxicity resulted in premature termination of its development. Here, we investigated whether TAK-875 directly inflicts toxicity on hepatocytes and explored its underlying mechanism of toxicity. TAK-875 decreased viability of 2D and 3D cultures of HepG2, a human hepatocarcinoma cell line, in concentration-(>50 mM) and time-dependent manners, both of which corresponded with ROS generation. An antioxidant, N-acetylcysteine, attenuated TAK-875-mediated hepatotoxicity, which confirmed the role of ROS generation. Of note, knockdown of GPR40 using siRNA abolished the hepatotoxicity of TAK-875 and attenuated ROS generation. In contrast, TAK-875 induced no cytotoxicity in fibroblasts up to 500 mM. Supporting the hepatotoxic potential of TAK-875, exposure to TAK-875 resulted in increased mortality of zebrafish larvae at 25 mM. Histopathological examination of zebrafish exposed to TAK-875 revealed severe hepatotoxicity as manifested by degenerated hypertrophic hepatocytes with cytoplasmic vacuolation and acentric nuclei, confirming that TAK-875 may induce direct hepatotoxicity and that ROS generation may be involved in a GPR40-dependent manner.
Original language | English |
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Pages (from-to) | 599-607 |
Number of pages | 9 |
Journal | Biomolecules and Therapeutics |
Volume | 26 |
Issue number | 6 |
DOIs | |
State | Published - Nov 2018 |
Bibliographical note
Funding Information:This work is supported by National Research Founda-
Funding Information:
This work is supported by National Research Foundation of Korea (Grant No. NRF-2015R1D1A1A01057931 and 2017R1A6A3A11034070).
Publisher Copyright:
© 2018, Korean Society of Applied Pharmacology. All rights reserved.
Keywords
- Fasiglifam
- G-protein coupled receptor 40
- GPR40
- Hepatotoxicity
- Reactive oxygen species
- Zebrafish