Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells Giuseppe Maulucci a , Bareket Daniel b , Ofir Cohen b , Yossef Avrahami b , Shlomo Sasson b, * a Istituto di Fisica, Universita Cattolica del Sacro Cuore, Rome, Italy b Department of Pharmacology, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel A R T I C L E I N FO Article history: Received 22 November 2015 Revised 23 February 2016 Accepted 9 March 2016 Available online 21 March 2016 Keywords: Beta cells Diabetes Eicosanoids Fatty aldehyde dehydrogenase Glutathione peroxidase Glutathione-S-transferase4- hydroxyalkenals 4-Hydroxynonenal Lipid peroxidation Phospholipase A A B ST R AC T Nutrient sensing mechanisms of carbohydrates, amino acids and lipids operate distinct path- ways that are essential for the adaptation to varying metabolic conditions. The role of nutrient-induced biosynthesis of hormones is paramount for attaining metabolic homeo- stasis in the organism. Nutrient overload attenuate key metabolic cellular functions and interfere with hormonal-regulated inter- and intra-organ communication, which may ul- timately 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 phe- nomenon, 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 pe- ripheral 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,β-unsaturated reactive 4-hydroxyalkenals that avidly form covalent adducts with nucleophilic moieties in proteins, phospholipids and nucleic acids. Numer- ous 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, Chemical compounds studied in this article:12-HETE (PubChem CID: 5283155); 15-HETE (PubChem CID: 280724); 4-HNA (PubChem CID: 0442150); 12- HpETE (PubChem CID: 5283175); 15-HpETE (PubChem CID: 6437084); 13-HpODE (PubChem CID: 5280720); 13-HODE (PubChem CID: 5282947); 4-Hydroxy- 2E,6Z-dodecadienal (PubChem CID: 71340423); 4-Hydroxyl-2E-hexenal (PubChem CID: 5283314); 4-Hydroxy-2E-nonenal (PubChem CID: 5283344); PGD2 (PubChem CID: 448457); PGE2 (PubChem CID: 5280360); PGF2α (PubChem CID: 5280363); PGH2 (PubChem CID: 445049); PGI2 (PubChem CID: 6436393). Abbreviations: 4-HDDE, 4-hydroxy-2E,6Z-dodecadienal; 4-HHE, 4-hydroxyl-2E-hexenal; 4-HNA, 4-hydroxynon-2-enoic acid; 4-HNE, 4-hydroxy-2E- nonenal; AGE, advanced glycation end products; ADH, alcohol dehydrogenase; AR, aldose reductase; ARE, antioxidant response element; CaMKII, Ca 2+ / calmodulin-dependent protein kinase II; COX, cyclooxygenase; DAG, diacylglycerol; EET, epoxyeicosatrienpic acid; EGF, epidermal growth factor; EGRFR, epidermal growth factor receptors; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinases; FALDH, fatty aldehyde dehydrogenase; FDGFR, platelet-derived growth factor receptor; FFA1, free fatty acid receptor 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GLP-1, glucagon-like peptide- 1; GP, generalized polarization index; GPx, glutathione peroxidase; GSH, glutathione; GSIS, glucose-stimulated insulin secretion; GST, glutathione-S- transferase; HETE, hydroxyeicosatetraenoic acid; HpETE, hydroperoxyeicosatetraenoic acid; HIF, hypoxia-inducible factor; HpODE, hydroperoxyoctadecadienoic acid; IKK, IκB kinase; IRS, insulin receptor substrate; JUNK, c-Jun N-terminal kinase; Keap1, Kelch-like ECH-associated protein; Lck, lymphocyte-specific protein tyrosine kinase; LT, leukotriene; LO, lipoxygenase; MAPK, mitogen-activated protein kinase; MAPKK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; MUFA, monounsaturated fatty acids; Nrf2, nuclear factor (erythroid-derived 2)-like 2; NOS, NO synthase; NOX, NADPH oxidase; NQO1, NAD(P)H:quinone oxidoreductase; PARP, poly(ADP-ribose)-polymerase; PKB/Akt, protein kinase B; PKC, protein kinase C; PDGFR, platelet- derived growth factor receptors; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PI3K, phosphatidylinositol-3-kinase; PLA2, phospholipase A2; PPARδ, peroxisome proliferator-activated receptor δ; PTEN, phosphatase and tensin homolog; PTP, protein tyrosine phosphatases; PUFA, polyunsaturated fatty acids; ROS, reactive oxygen species; SOD, superoxide dismutase; S6K1, p70 ribosomal protein S6 kinase; sEH, soluble epoxide hydrolase; SFA, saturated fatty acids; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; T2DM, type 2 diabetes mellitus; UCP, uncoupling protein; Xpo1, export protein exportin1. * Corresponding author. Department of Pharmacology, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001 Jerusalem, Israel. Tel.: +972 2 6758798; fax: +972 26758741. E-mail addresses: shlomo.sasson@mail.huji.ac.il (S. Sasson). http://dx.doi.org/10.1016/j.mam.2016.03.001 0098-2997/© 2016 Elsevier Ltd. All rights reserved. Molecular Aspects of Medicine 49 (2016) 49–77 Contents lists available at ScienceDirect Molecular Aspects of Medicine journal homepage: www.elsevier.com/locate/mam