title: Anti-diabetic effect of 3-hydroxy-2-naphthoic acid, an endoplasmic reticulum stress-reducing chemical chaperone.
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, IKKβ and IRS1 (S307) and restored insulin signaling cascade which involves insulin receptor β, IRS1 and Akt. 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 150mg/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.
authors.affiliation: Biocenter, Gyeonggi Institute of Science and Technology Promotion, Suwon, Gyeonggi-do 16229, South Korea.
authors.forename: Sun-mi
authors.initials: SM
authors.lastname: Park
authors.affiliation: Biocenter, Gyeonggi Institute of Science and Technology Promotion, Suwon, Gyeonggi-do 16229, South Korea.
authors.forename: Jungsook
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, South Korea. Electronic address: tnam@hanyang.ac.kr.
authors.forename: Tae-gyu
authors.initials: TG
authors.lastname: Nam
authors.affiliation: Biocenter, Gyeonggi Institute of Science and Technology Promotion, Suwon, Gyeonggi-do 16229, South Korea.
authors.forename: Jin-mo
authors.initials: JM
authors.lastname: Ku
authors.affiliation: Biocenter, Gyeonggi Institute of Science and Technology Promotion, Suwon, Gyeonggi-do 16229, South Korea. Electronic address: assylum@gstep.re.kr.
authors.forename: Kwiwan
authors.initials: K
authors.lastname: Jeong
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology; D051379:Mice; D009284:Naphthols / Q000494:pharmacology*; D047495:PPAR gamma / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D009284:Naphthols; D047495:PPAR gamma; D019308:Palmitic Acid; C021303:3-hydroxy-2-naphthoic acid
keywords: Beta cell death; Chemical chaperone; Diabetes mellitus; Endoplasmic reticulum stress; Insulin resistance; Unfolded protein response