Biomol Ther  
Fasiglifam (TAK-875), a G Protein-Coupled Receptor 40 (GPR40) Agonist, May Induce Hepatotoxicity Through Reactive Oxygen Species Generation in a GPR40-Dependent Manner
MinJeong Kim1,†, Gyo Jeong Gu2,†, Yun-Sook Koh1, Su-Hyun Lee3, Yi Rang Na2, Seung Hyeok Seok2,* and Kyung-Min Lim1,*
1College of Pharmacology, Ewha Womans University, Seoul 03760,
2Department of Microbiology and Immunology and Institute of Endemic Disease, Seoul National University College of Medicine, Seoul 03080, 3Biosolutions Co., Seoul 01811, Republic of Korea
E-mail: (Lim KM), (Seok SH)
Tel: +82-2-3277-3055 (Lim KM), +82-2-740-8302 (Seok SH)
Fax: +82-2-3277-3760 (Lim KM), +82-2-743-0881 (Seok SH)
The first two authors contributed equally to this work.
Received: November 1, 2017; Revised: January 11, 2018; Accepted: January 12, 2018; Published online: February 12, 2018.
© The Korean Society of Applied Pharmacology. All rights reserved.

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 μM) 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 μM. Supporting the hepatotoxic potential of TAK-875, exposure to TAK-875 resulted in increased mortality of zebrafish larvae at 25 μM. 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.
Keywords: Fasiglifam, Hepatotoxicity, Zebrafish, Reactive oxygen species, GPR40, G-protein coupled receptor 40

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