TAK-875 Mitigates <i>β</i>-Cell Lipotoxicity-Induced Metaflammation Damage through Inhibiting the TLR4-NF-<i>κ</i>B Pathway

Xide, Chen; Yan, Yuanli; Weng, Zhiyan; Chen, Chao; Lv, Miaoru; Lin, Qingwen; Du, Qiuxia; Shen, Xiaodong; Yang, Liyong

doi:10.1155/2019/5487962

Cited by 12 publications

(3 citation statements)

References 40 publications

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“…This was in order to avoid lipotoxicity, which may contribute to diabetes progression [ 56 , 57 ]. In fact, synthetic agonists were reported not to be lipotoxic in the diabetic milieu (owing to beneficial activation of GPR40) [ 58 , 59 ], but they eventually turned out toxic specifically to the liver. The accumulated body of evidence in this work suggests that CPL207280 is a peculiar GPR40 agonist, that significantly differs from other agonists, especially TAK-875 in terms of the structure and potency that determine liver safety in animal models.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey

et al. 2021

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GPR40 (FFAR1) is a promising target for the managing type 2 diabetes (T2D). The most advanced GPR40 agonist TAK-875 exhibited satisfactory glucose-lowering effects in phase II and III studies. However, the phase III studies of TAK-875 revealed drug-induced liver injury (DILI). It is unknown whether DILI is a consequence of a specific GPR40 agonist or is an inherent feature of all GPR40 agonists. CPL207280 is a novel GPR40 agonist that improves diabetes in Zucker Diabetic Fatty (ZDF) rats, Goto Kakizaki (GK) rats and db/db mice. In this report, the DILI-related toxicity of CPL207280 was compared directly with that of TAK-875. In vitro studies evaluating hepatic biliary transporter inhibition, mitochondrial function, and metabolic profiling were performed in hepatocytes from different species. The long term toxicity of CPL207280 was studied in vivo in rats and monkeys. Activity of CPL207280 was one order of magnitude lesser than that of TAK-875 for the inhibition of bile acid transporters. CPL207280 had a negligible effect on the hepatic mitochondria. In contrast to TAK-875, which was metabolized through toxic glucuronidation, CPL207280 was metabolized mainly through oxidation. No deleterious hepatic effects were observed in chronically treated healthy and diabetic animals. The study presents promising data on the feasibility of creating a liver-safe GPR40 agonist. Additionally, it can be concluded that DILI is not a hallmark of GPR40 agonists; it is linked to the intrinsic properties of an individual agonist.

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Section: Discussionmentioning

confidence: 99%

Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey

et al. 2021

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“…However, addition of fetuin‐A in the medium compensated for the absence of fetuin‐A secreted from β‐cells, resulting in reduced insulin secretion and a higher percentage of apoptotic cells. Besides fetuin‐A, TLR4, and NF‐κB, play a key role in lipotoxicity induced β‐cell damage, and inhibition of the TLF4‐NF‐κB pathway inhibits apoptosis and improves insulin secretion from β‐cells (Chen et al, 2019; Eldor et al, 2013). Blocking of TLR4 and NF‐κB improved the survivability of MIN6 cells treated with palmitate and palmitate + fetuin‐A, providing credence to our hypothesis that palmitate inflicted apoptosis in MIN6 involved not only fetuin‐A but also the TLR4‐NF‐κB pathway.…”

Section: Discussionmentioning

confidence: 99%

Fetuin‐A excess expression amplifies lipid induced apoptosis and β‐cell damage

Mukhuty

Fouzder

Kundu

2021

Journal Cellular Physiology

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Fetuin-A, a hepato-adipokine, is associated with lipid-mediated islet inflammation and inflicts β-cell death but the underlying mechanisms are still unclear. In an earlier report, it was shown that fetuin-A promotes lipid-induced insulin resistance by acting as an endogenous ligand of toll like receptor 4. Recently, we have also reported that β-cells secrete fetuin-A on stimulation by palmitate causing β-cell dysfunction. The aim of this study was twofold: (a) screening the role of fetuin-A in survival of murine β-cells, and (b) to validate the effect of fetuin-A release and lipid induced apoptosis in mouse insulinoma cell line MIN6. Excess of lipid and fetuin-A in circulation induced significant deterioration of islet histoarchitecture and impeded insulin secretion by 2.7 ± 0.5-folds in 20 weeks high fat diet mice. Administration of fetuin-A (0.7 mg/g) along with 4 weeks of HFD produced similar results as 20 weeks of high fat feeding. Treating high doses of palmitate alone (0.50 mM) as well as in combination with fetuin-A (100 µg/ml) for 24 h inflicted apoptosis in MIN6 through the mitochondrial pathway. Knockdown of fetuin-A gene partially inhibited palmitate inflicted apoptosis in MIN6 by 1.83 ± 0.25 times, however, fetuin-A when added in the medium caused re-emergence of apoptosis. Notably, apoptosis induced by palmitate conditioned media from MIN6, 3T3L1, and HepG2, was partially inhibited in fetuin-A KD MIN6. These results confirmed the critical role of circulatory fetuin-A and β-cell secreted fetuin-A in β-cell dysfunction and apoptosis under hyperlipidemic conditions.

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“…Immunological responses, metabolic adaptation, and mitochondrial dysfunction, in particular, are the hallmarks of inflammation-induced changes. Metabolic inflammation induced during lipotoxicity as seen in diabetes and obesity has also been implicated in the development of β-cell toxicity and metabolic complications ( Chen et al, 2019 ). High glucose and fatty acid levels (glucolipotoxicity) in diabetes as well as exposure to pro-inflammatory bacterial endotoxin, lipopolysaccharide (LPS), could cause destruction of the pancreatic cells and alterations in mitochondrial function ( Alnahdi et al, 2019a , 2020 ; Xu et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Alterations in Inflammatory Cytokines and Redox Homeostasis in LPS-Induced Pancreatic Beta-Cell Toxicity and Mitochondrial Stress: Protection by Azadirachtin

John

Raza

2022

Front. Cell Dev. Biol.

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Inflammation and redox imbalance are hallmarks of cancer, diabetes, and other degenerative disorders. Pathophysiological response to these disorders leads to oxidative stress and mitochondrial dysfunction by alterations and reprogramming in cellular signaling and metabolism. Pancreatic beta cells are very sensitive to the inflammatory and altered nutrient signals and hence play a crucial role in diabetes and cancer. In this study, we treated insulin-secreting pancreatic beta cells, Rin-5F, with the bacterial endotoxin, LPS (1 μg/ml) to induce an inflammatory response in vitro and then treated the cells with a known anti-inflammatory, anticancer and antioxidant phytochemical, azadirachtin (AZD, 25 µM for 24 h). Our results demonstrated lipid peroxidation and nitric oxide production causing increased nitro/oxidative stress and alterations in the activities of anti-oxidant enzymes, superoxide dismutase and catalase after LPS treatment. Pro-inflammatory responses caused by translocation of nuclear factor kappa B and release of inflammatory cytokines were also observed. These changes were accompanied by GSH-dependent redox imbalance and alterations in mitochondrial membrane potential and respiratory complexes enzyme activities leading to mitochondrial respiratory dysfunction, reduced ATP synthesis, and intrinsic caspase-9 mediated apoptosis. Caspase-9 was activated due to alterations in Bcl-2 and Bax proteins and release of cytochrome c into the cytosol. The activities of oxidative stress-sensitive mitochondrial matrix enzymes, aconitase, and glutamate dehydrogenase were also inhibited. Treatment with AZD showed beneficial effects on the recovery of antioxidant enzymes, inflammatory responses, and mitochondrial functions. GSH-dependent redox homeostasis also recovered after the treatment with AZD. This study may help in better understanding the etiology and pathogenesis of inflammation-induced disorders in pancreatic beta cells to better manage therapeutic strategies.

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TAK-875 Mitigates β-Cell Lipotoxicity-Induced Metaflammation Damage through Inhibiting the TLR4-NF-κB Pathway

Cited by 12 publications

References 40 publications

Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey

Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey

Fetuin‐A excess expression amplifies lipid induced apoptosis and β‐cell damage

Alterations in Inflammatory Cytokines and Redox Homeostasis in LPS-Induced Pancreatic Beta-Cell Toxicity and Mitochondrial Stress: Protection by Azadirachtin

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