Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8293013 | Biochemical and Biophysical Research Communications | 2018 | 6 Pages |
Abstract
Activating transcription factor 6α (ATF6α) as a transducer in unfolded protein response (UPR), plays an important role in liver glucose metabolism and insulin resistance. Thus, targeting ATF6α activation has been proposed to be a potential strategy for anti-T2DM drug discovery. Here, we determined that small molecule 2-[5-[1-(4-chlorophenoxy)ethyl]-4-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)acetamide (TSPA) functioned as an ATF6α translocation inducer effectively promoting ATF6α translocation into nucleus and ameliorating glucose homeostasis on db/db mice. TSPA promoted ATF6α translocation into nucleus without incresing C/EBP-homologous protein (CHOP) expression. TSPA restored the tunicamycin (TM)-stimulated insulin receptor (IR) desensitization through ATF6α activation, inhibited gluconeogenesis and efficiently improved glucose homeostasis on db/db mice. Furthermore, TSPA protected insulin pathway involving p38/X-box binding protein 1s (Xbp1s)/ER chaperones signaling pathway. Our current study has determined that ATF6α was a promising therapeutic target and also highlighted the potential of TSPA in the treatment of type 2 diabetes mellitus (T2DM).
Keywords
G6PaseCREBATF6αPEPCKUPROGTTT2DMGRP94ATF6PTTCrtERADtunicamycinXBP1SC/EBP-homologous proteinCNxIRE1αpyruvate tolerance testOral glucose tolerance testAktER stressEndoplasmic reticulum associated degradationCHOPType 2 diabetes mellitusendoplasmic reticulumphosphoenolpyruvate carboxykinaseactivating transcription factor 6Insulin resistanceUnfolded protein responsecAMP response element binding proteinprotein kinase BPERKcalreticulincalnexinglucose-6-phosphataseGlucose regulated protein 94insulin receptor
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Authors
Tingting Zhou, Yanhua Cheng, Wenzhong Yan, Xiaofan Shi, Xin Xu, Jinpei Zhou, Jian Li, Jing Chen, Xu Shen,