title: Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation.
abstract: OBJECTIVE
  Membrane phospholipids are the major intracellular source for fatty acid-derived mediators, which regulate myriad cell functions. We showed previously that high glucose levels triggered the hydrolysis of polyunsaturated fatty acids from beta cell phospholipids. These fatty acids were subjected to free radical-catalysed peroxidation to generate the bioactive aldehyde 4-hydroxy-2E-nonenal (4-HNE). The latter activated the nuclear peroxisome proliferator-activated receptor-δ (PPARδ), which in turn augmented glucose-stimulated insulin secretion. The present study aimed at investigating the combined effects of glucose and fatty acid overload on phospholipid turnover and the subsequent generation of lipid mediators, which affect insulin secretion and beta cell viability.
  
  
  METHODS
  INS-1E cells were incubated with increasing glucose concentrations (5-25 mmol/l) without or with palmitic acid (PA; 50-500 μmol/l) and taken for fatty acid-based lipidomic analysis and functional assays. Rat isolated islets of Langerhans were used similarly.
  
  
  RESULTS
  PA was incorporated into membrane phospholipids in a concentration- and time-dependent manner; incorporation was highest at 25 mmol/l glucose. This was coupled to a rapid exchange with saturated, mono-unsaturated and polyunsaturated fatty acids. Importantly, released arachidonic acid and linoleic acid were subjected to peroxidation, resulting in the generation of 4-HNE, which further augmented insulin secretion by activating PPARδ in beta cells. However, this adaptive increase in insulin secretion was abolished at high glucose and PA levels, which induced endoplasmic reticulum stress, apoptosis and cell death.
  
  
  CONCLUSIONS
  These findings highlight a key role for phospholipid remodelling and fatty acid peroxidation in mediating adaptive and cytotoxic interactions induced by nutrient overload in beta cells.
authors: Department of Pharmacology, Institute for Drug Research, Faculty of Medicine, The Hebrew University, Jerusalem, 9112102, Israel.
authors: Guy
authors: G
authors: Cohen
authors: Ofer
authors: O
authors: Shamni
authors: Yossef
authors: Y
authors: Avrahami
authors: Ofir
authors: O
authors: Cohen
authors: Esther C
authors: EC
authors: Broner
authors: Natalie
authors: N
authors: Filippov-Levy
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: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival; D005227:Fatty Acids / Q000737:chemistry; D005609:Free Radicals; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D047494:PPAR delta / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D019308:Palmitic Acid / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D005609:Free Radicals; D047494:PPAR delta; D047495:PPAR gamma; D010743:Phospholipids; D019308:Palmitic Acid