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

Journal Article · Tue May 15 04:00:00 EDT 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.04.025· OSTI ID:23125264

Zhou, Tingting ^[1]; Cheng, Yanhua ^[2]; Yan, Wenzhong ^[3]; Shi, Xiaofan; Xu, Xin ^[4]; Zhou, Jinpei ^[2]; Li, Jian ^[3]; Chen, Jing ^[4]; Shen, Xu ^[4]

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1. Wuxi School of Medicine, Jiangnan University, 1800 Lihu Road, Wuxi 214122 (China)
2. School of Pharmacy, China Pharmaceutical University, Jiangsu, Nanjing 210009 (China)
3. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237 (China)
4. CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203 (China)

Highlights: • 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. 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).

• OSTI ID: 23125264
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 4 Vol. 499; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACETAMIDE
BIOLOGICAL RECOVERY
DIABETES MELLITUS
GLUCOSE
INSULIN
RECEPTORS
TRANSCRIPTION FACTORS