TSPA as a novel ATF6α translocation inducer efficiently ameliorates insulin sensitivity restoration and glucose homeostasis in db/db mice

• Published in: Biochemical and biophysical research communications 2018-05, Vol.499 (4), p.948-953
• Main Authors: Zhou, Tingting, Cheng, Yanhua, Yan, Wenzhong, Shi, Xiaofan, Xu, Xin, Zhou, Jinpei, Li, Jian, Chen, Jing, Shen, Xu
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ACETAMIDE; ATF6α; BIOLOGICAL RECOVERY; DIABETES MELLITUS; ER stress; GLUCOSE; INSULIN; Insulin resistance; RECEPTORS; T2DM; TRANSCRIPTION FACTORS; TSPA
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2018.04.025

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). •Targeting ATF6α activation is supposed to be a potential strategy for anti-T2DM drug discovery.•TSPA functioned as an ATF6α translocation inducer ameliorating glucose homeostasis on db/db mice.•Our current study has highlighted the potential of TSPA in the treatment of T2DM.