Fasiglifam (TAK-875), a G Protein-Coupled Receptor 40 (GPR40) Agonist, May Induce Hepatotoxicity through Reactive Oxygen Species Generation in a GPR40-Dependent Manner

Kim, Minjeong; Gu, Gyo Jeong; Koh, Yun Sook; Lee, Sang Ho; Na, Yi Rang; Seok, Seonho; Lim, Kyung Min

doi:10.4062/biomolther.2017.225

Cited by 21 publications

(11 citation statements)

References 46 publications

(50 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both GW9508 and TAK-875 effectively agonize Gpr40 but they also activate other G protein receptors. Kim et al showed that high doses of TAK-875 (50, 100, 250 and 500 µM) dose-responsively induce the death of HepG2 cells, 25 which was found to be associated with the induction of hepatic ROS generation. Philippe et al report that a high dose of GW9508 (100 µM) decreases the proliferation of osteoblast precursor cell line RAW264.7.…”

Section: Discussionmentioning

confidence: 99%

<p>Agonism of Gpr40 Protects the Capacities of Epidermal Stem Cells (ESCs) Against Ultraviolet-B (UV-B)</p>

Sun

Li²,

et al. 2020

DDDT

View full text Add to dashboard Cite

Introduction: Skin damage due to overexposure to ultraviolet B (UV-B) radiation can lead to the development of cancers and reduce the skin's functionality as a vital protective barrier. Epidermal stem cells (ESCs) are pluripotent cells responsible for skin regeneration and healing. Upon exposure to UV-B radiation, ESCs produce excess amounts of reactive oxygen species (ROS) and inflammatory cytokines. However, the functional protection of ESCs is not fully explored. G-protein coupled G protein-coupled receptor 40 (Gpr40) is a free fatty acid receptor that is emerging as a potential treatment target for various diseases. Gpr40 has been found to be expressed in various cell types. Methods: ESCs were exposed to UV-B at the intensities of 25, 50, and 100 mJ/cm 2 for 24 h using TL 20 W/12 RS UV lamps. ESCs were treated with UV-B at 50 mJ/cm 2 in the presence or absence of 25 or 50 µM of the Gpr40 agonist GW9508 for 24 h. The gene expression of the Wnt1 pathway and proinflammatory cytokines were evaluated. To antagonize Gpr40 expression, ESCs were treated with 10 µM GW1100. Results: Our findings demonstrate that Gpr40 agonism can reduce the production of ROS as well as the expression of interleukins 1β and 8, two key proinflammatory cytokines. We demonstrate that agonism of Gpr40 can rescue the reduction in integrin β1 and Krt19 induced by UV-B exposure, thereby improving the capacities of ESCs to resist UV-B damage. Moreover, we show that the effects of Gpr40 agonism observed in our experiments are mediated through the Wnt/β-catenin canonical signaling pathway, as evidenced by the expression of Wnt1 and cyclin D1. Conclusion: Our findings present evidence of the role of Gpr40 agonism in mediating the protective capacities of ESCs against insult from UV-B radiation.

show abstract

Section: Discussionmentioning

confidence: 99%

<p>Agonism of Gpr40 Protects the Capacities of Epidermal Stem Cells (ESCs) Against Ultraviolet-B (UV-B)</p>

Sun

Li²,

et al. 2020

DDDT

View full text Add to dashboard Cite

show abstract

“…While GPR40 agonists, palmitic acid, and oleic acid act through G q/11 -mediated mechanisms, the synthetic agonist TAK-875 can act as a β-arrestin2-biased agonist, engaging β-arrestin2-dependent signaling to induce the insulinotropic activity of GPR40 ( 13 ). The biased GPR40 activation has shown a promising potential as a therapeutic target to enhance insulin secretion in T2D ( 79 ), but phase III clinical trials with TAK-875 were recently terminated due to signs of liver toxicity in patients ( 81 ). Therefore, therapies based on GPR40 agonism provide an attractive alternative in the discovery of antidiabetic drugs, but further studies are needed to determine if potential side effects induced by this approach can be avoided.…”

Section: Gpcr Signaling Pathways In Metabolismmentioning

confidence: 99%

Metabolic Functions of G Protein-Coupled Receptors and β-Arrestin-Mediated Signaling Pathways in the Pathophysiology of Type 2 Diabetes and Obesity

Souza

Sun

2021

Front. Endocrinol.

View full text Add to dashboard Cite

Seven transmembrane receptors (7TMRs), often termed G protein-coupled receptors (GPCRs), are the most common target of therapeutic drugs used today. Many studies suggest that distinct members of the GPCR superfamily represent potential targets for the treatment of various metabolic disorders including obesity and type 2 diabetes (T2D). GPCRs typically activate different classes of heterotrimeric G proteins, which can be subgrouped into four major functional types: Gαs, Gαi, Gαq/11, and G12/13, in response to agonist binding. Accumulating evidence suggests that GPCRs can also initiate β-arrestin-dependent, G protein-independent signaling. Thus, the physiological outcome of activating a certain GPCR in a particular tissue may also be modulated by β-arrestin-dependent, but G protein-independent signaling pathways. In this review, we will focus on the role of G protein- and β-arrestin-dependent signaling pathways in the development of obesity and T2D-related metabolic disorders.

show abstract

“…It is expressed in the insulin-secreting cells where its ligands augment the elevated plasma glucose-induced secretion of insulin [45]. In Phase III clinical trials, Takeda Pharmaceuticals' GPR40 agonist, fasiglifam (TAK-875) significantly improved hyperglycemia without hypoglycemia and weight gain but was discontinued because of unexpected liver toxicity [46]. More GPR40 modulators have been disclosed in WO/2004/041266 (Takeda Pharmaceutical Co., Ltd), WO/2007/033002 (Amgen, Inc.), and WO/2009/157418 (Daiichi Sankyo Co. Ltd), but in the present application Boehringer Ingelheim has improved on the compounds disclosed in its own application WO/2013/178575 in terms of potency, solubility and chemical stability at acidic pH.…”

Section: Wo/2018/086530mentioning

confidence: 99%

Patent Highlights April–May 2018

Mucke¹

2018

Pharm. Pat. Anal.

View full text Add to dashboard Cite

Inflammatory bowel diseases seem to be triggered by an intestinal epithelial dysfunction, probably in response to danger signals that might only suggest the presence of pathogens but nevertheless amplify and sustain the release of proinflammatory cytokines. There is considerable evidence that activation of purinergic receptors by nucleotides such as ATP and UTP, constitutes at least part of these signals and not only in the intestinal tract [1,2]. This signaling is terminated by nucleoside triphosphate diphosphohydrolases (e.g., NTPDase-1, CD39). NTPDases are expressed by immunosuppressive supTh17 T-helper cells [3]. The inventors have demonstrated that NTPDase-8 is expressed on epithelial cells at the apical surface of the mouse and human colon. Although its gross effect on nucleotide hydrolysis in the entire intestine is minimal, its precise localization makes it a most important regulator of intestinal inflammation. Degradation of nucleotides by apyrase, selective blockade of P2Y6 receptors by MRS 2578 or knockout of the P2Y2 receptor protects mice against dextran sodium sulfate-induced colitis and decreases epithelial permeability and chemokine secretion. Selective P2Y2 and P2Y6 ligands have been described [4] but antagonists are rare.

show abstract

Fasiglifam (TAK-875), a G Protein-Coupled Receptor 40 (GPR40) Agonist, May Induce Hepatotoxicity through Reactive Oxygen Species Generation in a GPR40-Dependent Manner

Cited by 21 publications

References 46 publications

<p>Agonism of Gpr40 Protects the Capacities of Epidermal Stem Cells (ESCs) Against Ultraviolet-B (UV-B)</p>

<p>Agonism of Gpr40 Protects the Capacities of Epidermal Stem Cells (ESCs) Against Ultraviolet-B (UV-B)</p>

Metabolic Functions of G Protein-Coupled Receptors and β-Arrestin-Mediated Signaling Pathways in the Pathophysiology of Type 2 Diabetes and Obesity

Patent Highlights April–May 2018

Contact Info

Product

Resources

About