title: Role of lipid peroxidation and PPAR-δ in amplifying glucose-stimulated insulin secretion.
abstract: OBJECTIVE
  Previous studies show that polyunsaturated fatty acids (PUFAs) increase the insulin secretory capacity of pancreatic β-cells. We aimed at identifying PUFA-derived mediators and their cellular targets that are involved in the amplification of insulin release from β-cells preexposed to high glucose levels.
  
  
  METHODS
  The content of fatty acids in phospholipids of INS-1E β-cells was determined by lipidomics analysis. High-performance liquid chromatography was used to identify peroxidation products in β-cell cultures. Static and dynamic glucose-stimulated insulin secretion (GSIS) assays were performed on isolated rat islets and/or INS-1E cells. The function of peroxisome proliferator-activated receptor-δ (PPAR-δ) in regulating insulin secretion was investigated using pharmacological agents and gene expression manipulations.
  
  
  RESULTS
  High glucose activated cPLA(2) and, subsequently, the hydrolysis of arachidonic and linoleic acid (AA and LA, respectively) from phospholipids in INS-1E cells. Glucose also increased the level of reactive oxygen species, which promoted the peroxidation of these PUFAs to generate 4-hydroxy-2E-nonenal (4-HNE). The latter mimicked the GSIS-amplifying effect of high glucose preexposure and of the PPAR-δ agonist GW501516 in INS-1E cells and isolated rat islets. These effects were blocked with GSK0660, a selective PPAR-δ antagonist, and the antioxidant N-acetylcysteine or by silencing PPAR-δ expression. High glucose, 4-HNE, and GW501516 also induced luciferase expression in a PPAR-δ-mediated transactivation assay. Cytotoxic effects of 4-HNE were observed only above the physiologically effective concentration range.
  
  
  CONCLUSIONS
  Elevated glucose levels augment the release of AA and LA from phospholipids and their peroxidation to 4-HNE in β-cells. This molecule is an endogenous ligand for PPAR-δ, which amplifies insulin secretion in β-cells.
authors: Department of Pharmacology, School of Pharmacy, Faculty of Medicine, Institute for Drug Research, Hebrew University, Jerusalem, Israel.
authors: Guy
authors: G
authors: Cohen
authors: Yael
authors: Y
authors: Riahi
authors: Ofer
authors: O
authors: Shamni
authors: Michel
authors: M
authors: Guichardant
authors: Chryssostomos
authors: C
authors: Chatgilialoglu
authors: Carla
authors: C
authors: Ferreri
authors: Nurit
authors: N
authors: Kaiser
authors: Shlomo
authors: S
authors: Sasson
mesh_terms: D000447:Aldehydes / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D020868:Gene Silencing; D005849:Gerbillinae; D054513:Group IV Phospholipases A2 / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D047494:PPAR delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D046509:Tissue Culture Techniques
chemical_list: D000447:Aldehydes; D005231:Fatty Acids, Unsaturated; D007328:Insulin; D047494:PPAR delta; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D054513:Group IV Phospholipases A2; C027576:4-hydroxy-2-nonenal