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Anti-diabetic effect of 3-hydroxy-2-naphthoic acid, an endoplasmic reticulum stress-reducing chemical chaperone

Title
Anti-diabetic effect of 3-hydroxy-2-naphthoic acid, an endoplasmic reticulum stress-reducing chemical chaperone
Author
남태규
Keywords
Diabetes mellitus; Chemical chaperone; Endoplasmic reticulum stress; Unfolded protein response; Insulin resistance; Beta cell death
Issue Date
2016-05
Publisher
ELSEVIER SCIENCE BV
Citation
EUROPEAN JOURNAL OF PHARMACOLOGY, v. 779, Page. 157-167
Abstract
Lots of experimental and clinical evidences indicate that chronic exposure to saturated fatty acids and high level of glucose is implicated in insulin resistance, beta cell failure and ultimately type 2 diabetes. In this study, we set up cell-based experimental conditions to induce endoplasmic reticulum (ER) stress and insulin resistance using high concentration of palmitate (PA). Hydroxynaphthoic acids (HNAs) were formerly identified as novel chemical chaperones to resolve ER stress induced by tunicamycin. In this study, we found the compounds have the same suppressive effect on PA-induced ER stress in HepG2 cells. The representing compound, 3-HNA reduced PA-induced phosphorylation of JNK, IKKf3 and IRS1 (S307) and restored insulin signaling cascade which involves insulin receptor f3, IRS1 and Alt. The insulin sensitizing effect of 3-HNA was confirmed in 3T3-L1 adipocytes, where the compound augmented insulin signaling and glucose transporter 4 (GLUT4) membrane translocation. 3-HNA also protected the pancreatic beta cells from PA-induced apoptosis by reducing ER stress. Upon 3-HNA treatment to ob/ob mice at 150 mg/kg/day dosage, the diabetic parameters including glucose tolerance and systemic insulin sensitivity were significantly improved. Postmortem examination showed that 3-HNA markedly reduced ER stress and insulin resistance in the liver tissues and it sensitized insulin signaling in the liver and the skeletal muscle. Our results demonstrated that 3-HNA can sensitize insulin signaling by coping with lipotoxicity-induced ER stress as a chemical chaperone and suggested it holds therapeutic potential for insulin resistance and type 2 diabetes. (C) 2016 Elsevier B.V. All rights reserved.
URI
https://www.sciencedirect.com/science/article/pii/S0014299916301455http://hdl.handle.net/20.500.11754/53828
ISSN
0014-2999; 1879-0712
DOI
10.1016/j.ejphar.2016.03.023
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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