کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
11025681 | 1666535 | 2018 | 46 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Comparative hepatic transcriptome analyses revealed possible pathogenic mechanisms of fasiglifam (TAK-875)-induced acute liver injury in mice
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کلمات کلیدی
nESOATPsFFAR4-PBAConANtcpNa+-taurocholate co-transporting polypeptideDrug-induced liver injury (DILI)BSEPMrp2TLRCCl4ALTGPRConcanavalin ADAMPsFDRDEXG-protein coupled receptor - G-پروتئین همراه گیرندهDrug-induced liver injury - آسیب کبدی ناشی از مواد مخدرAlanine aminotransferase - آلانین آمینوترانسفراز4-phenylbutyric acid - اسید 4-فنیل بوتیریکdamage-associated molecular patterns - الگوهای مولکولی مرتبط با آسیبinterleukin - اینترلوکینGene Set Enrichment Analysis - تجزیه و تحلیل غنی سازی مجموعه ژنیToll-like receptor - تیالآرDexamethasone - دگزامتازونDILI - دیلیMicroarray - ریزآرایهendoplasmic reticulum - شبکه آندوپلاسمی DEG - شماfalse discovery rate - میزان کشف کاذبnormalized enrichment score - نمره غنی سازی نرمال شدهGene ontology - هستیشناسی ژنیmultidrug resistance-associated protein 2 - پروتئین مرتبط با مقاومت چند دارویی 2Organic anion transporting polypeptides - پلیپپتید های حمل آنیون های آلیBile salt export pump - پمپ صادرات نمک صفرDifferentially expressed gene - ژن بیان شده متفاوت استCarbon tetrachloride - کربن تتراکلریدHPLC - کروماتوگرافی مایعی کاراhigh-performance liquid chromatography - کروماتوگرافی مایعی کاراfree fatty acid receptor - گیرنده اسید چرب آزاد
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم محیط زیست
بهداشت، سم شناسی و جهش زایی
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چکیده انگلیسی
Fasiglifam (TAK-875), a G protein-coupled receptor 40 (GPR40) agonist, was a drug candidate for type 2 diabetes. However, its development was terminated in phase 3 trials due to liver safety concerns. Although TAK-875 was reported to inhibit hepatobiliary transporters and disturb bile acid disposition, pathogenic mechanisms of TAK-875-induced liver injury are not fully understood. In this study, we sought to identify the mechanisms with a hepatic genome-wide transcriptomic analysis in a murine model. We demonstrated that, among the three GPR40 agonists, TAK-875, AMG-837, and TUG-770, only TAK-875 induced acute liver injury in mice. Transcriptome profiles of TAK-875-exposed liver was compared with those of non-hepatotoxic analogues AMG-837 and TUG-770 as negative controls and those of classical hepatotoxicants concanavalin A and carbon tetrachloride as positive controls. The comparative hepatic transcriptome analyses revealed the enrichment of genes involved in inflammation, endoplasmic reticulum (ER) stress, apoptosis, and hepatic lipid accumulation, suggesting that these events play pathophysiologic roles in the development of TAK-875-induced liver injury. These results were validated by quantitative PCR with significant changes in chemokines, danger signals, ER stress mediators, proapoptotic factors, and hepatic steatosis markers only in TAK-875-exposed liver. Pretreatment of TAK-875-administered mice with an ER stress inhibitor 4-phenylbutyric acid (4-PBA) alleviated the liver injury. Consistent with the in vivo study, pretreatment of HepG2 cells with 4-PBA significantly improved the decrease of cell viability induced by TAK-875. In conclusion, by a comprehensive transcriptomic analysis, we found multiple possible processes that contribute to TAK-875-induced acute liver injury in mice.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Chemico-Biological Interactions - Volume 296, 25 December 2018, Pages 185-197
Journal: Chemico-Biological Interactions - Volume 296, 25 December 2018, Pages 185-197
نویسندگان
Yuya Urano, Shingo Oda, Koichi Tsuneyama, Tsuyoshi Yokoi,