Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation.

AIMS/HYPOTHESIS: 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/INTERPRETATION: 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.

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells.

Nutrient sensing mechanisms of carbohydrates, amino acids and lipids operate distinct pathways that are essential for the adaptation to varying metabolic conditions. The role of nutrient-induced biosynthesis of hormones is paramount for attaining metabolic homeostasis in the organism. Nutrient overload attenuate key metabolic cellular functions and interfere with hormonal-regulated inter- and intra-organ communication, which may ultimately lead to metabolic derangements. Hyperglycemia and high levels of saturated free fatty acids induce excessive production of oxygen free radicals in tissues and cells. This phenomenon, which is accentuated in both type-1 and type-2 diabetic patients, has been associated with the development of impaired glucose tolerance and the etiology of peripheral complications. However, low levels of the same free radicals also induce hormetic responses that protect cells against deleterious effects of the same radicals. Of interest is the role of hydroxyl radicals in initiating peroxidation of polyunsaturated fatty acids (PUFA) and generation of α,ß-unsaturated reactive 4-hydroxyalkenals that avidly form covalent adducts with nucleophilic moieties in proteins, phospholipids and nucleic acids. Numerous studies have linked the lipid peroxidation product 4-hydroxy-2E-nonenal (4-HNE) to different pathological and cytotoxic processes. Similarly, two other members of the family, 4-hydroxyl-2E-hexenal (4-HHE) and 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), have also been identified as potential cytotoxic agents. It has been suggested that 4-HNE-induced modifications in macromolecules in cells may alter their cellular functions and modify signaling properties. Yet, it has also been acknowledged that these bioactive aldehydes also function as signaling molecules that directly modify cell functions in a hormetic fashion to enable cells adapt to various stressful stimuli. Recent studies have shown that 4-HNE and 4-HDDE, which activate peroxisome proliferator-activated receptor δ (PPARδ) in vascular endothelial cells and insulin secreting beta cells, promote such adaptive responses to ameliorate detrimental effects of high glucose and diabetes-like conditions. In addition, due to the electrophilic nature of these reactive aldehydes they form covalent adducts with electronegative moieties in proteins, phosphatidylethanolamine and nucleotides. Normally these non-enzymatic modifications are maintained below the cytotoxic range due to efficient cellular neutralization processes of 4-hydroxyalkenals. The major neutralizing enzymes include fatty aldehyde dehydrogenase (FALDH), aldose reductase (AR) and alcohol dehydrogenase (ADH), which transform the aldehyde to the corresponding carboxylic acid or alcohols, respectively, or by biding to the thiol group in glutathione (GSH) by the action of glutathione-S-transferase (GST). This review describes the hormetic and cytotoxic roles of oxygen free radicals and 4-hydroxyalkenals in beta cells exposed to nutritional challenges and the cellular mechanisms they employ to maintain their level at functional range below the cytotoxic threshold.