title: Repression of sterol regulatory element-binding protein 1-c is involved in the protective effects of exendin-4 in pancreatic β-cell line.
abstract: Exendin-4 (Ex-4), a long-acting agonist of glucagon-like peptide-1 receptor, is a novel anti-diabetic drug that prevents β-cells against various toxicities. However, the mechanism and molecules mediating the protection procession of Ex-4 are not fully understood. We investigated the protective effect of Ex-4 against lipotoxicity, mediated by a repression of sterol regulatory element-binding protein (SREBP)-1c, a regulator of genes expression involved in fat and cholesterol synthesis. To observe the effect of Ex-4, we evaluated glucose-stimulated insulin secretion (GSIS) and apoptosis in the MIN6 pancreatic β-cell line, which were cultured in DMEM medium containing 500 μM palmitate, with or without 10 nM Ex-4. We also examined the roles of SREBP-1c in lipotoxicity model by knockdown with si-RNA. Treatment with Ex-4 improved insulin secretion and survival as well as reduced SREBP-1c expression and activity in palmitate-treated MIN6 cells. This improvement was accompanied with an upregulation of PI3K/Akt signaling pathway, and LY294.002, a specific inhibitor of PI3 kinase, abrogated effects of Ex-4 on insulin secretion. Moreover, SREBP-1c in nuclei was increased by the inhibition of PI3 kinase. Lipotoxic effects of palmitate in the insulin secretion and apoptosis were significantly prevented by SREBP-1 knockdown. In conclusion, Ex-4 protects β-cell against palmitate-induced β-cell dysfunction and apoptosis, by inhibiting SREBP-1c expression and activity through the PI3K/Akt signaling pathway.
authors: Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors: Seok-Woo
authors: SW
authors: Hong
authors: Jinmi
authors: J
authors: Lee
authors: Se Eun
authors: SE
authors: Park
authors: Eun-Jung
authors: EJ
authors: Rhee
authors: Cheol-Young
authors: CY
authors: Park
authors: Ki-Won
authors: KW
authors: Oh
authors: Sung-Woo
authors: SW
authors: Park
authors: Won-Young
authors: WY
authors: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D019610:Cytoprotection; D000077270:Exenatide; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D019308:Palmitic Acid / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*
chemical_list: D002867:Chromones; D000077270:Exenatide; D005947:Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D009025:Morpholines; D019308:Palmitic Acid; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D014688:Venoms; C497388:Srebf1 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one