Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8341462 | Molecular Aspects of Medicine | 2016 | 29 Pages |
Abstract
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,β-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.
Keywords
PI3KEGFCOX4-HNE4-hydroxynonenalNrf2GSHGSTADHGPXGAPDHmTORERKNOSMUFASFAPTPIRSCaMKIINO synthaseSNAREGLP-1PKCIKKPARPHIFS6K1PLA2T2DMNQO1PDGFRLCKPPARδPIP34-HHEGSISKelch-like ECH-associated proteinUCPXPO1MAPKKFFA1HpODEpoly(ADP-ribose)-polymerase4-HDDEkeap1c-Jun N-terminal kinaseCa2+/calmodulin-dependent protein kinase IIIκB kinaseMAPKNAD(P)H:quinone oxidoreductaseNOxp70 ribosomal protein S6 kinasePKB/AKTROSsEHFatty aldehyde dehydrogenaseAldose reductasecyclooxygenasephospholipase A2hydroperoxyeicosatetraenoic acidhydroperoxyoctadecadienoic acidhydroxyeicosatetraenoic acidPolyunsaturated fatty acidsPUFAsaturated fatty acidsmonounsaturated fatty acidsAlcohol dehydrogenaseinsulin receptor substrateNADPH oxidaseeicosanoidsDiabetesGlucose-stimulated insulin secretionEETType 2 diabetes mellitusdiacylglycerolDAGSODBeta cellsAgeSuperoxide dismutaseendoplasmic reticulumepidermal growth factorantioxidant response elementFALDHHypoxia-inducible factornuclear factor (erythroid-derived 2)-like 2phosphatase and tensin homologphosphatidylinositol (3,4,5)-trisphosphatephosphatidylinositol-3-kinasephospholipase ALeukotrienelipoxygenaseAdvanced glycation end productsHPETEmammalian target of rapamycinAREHETESoluble epoxide hydrolaseLipid peroxidationprotein tyrosine phosphataseslymphocyte-specific protein tyrosine kinaseUncoupling proteinprotein kinase BProtein kinase Cmitogen-activated protein kinasemitogen-activated protein kinase kinaseglucagon-like peptide-1Ptenextracellular signal-regulated kinasesGlutathioneglutathione-S-transferaseglutathione peroxidaseglyceraldehyde-3-phosphate dehydrogenaseReactive oxygen speciesFree fatty acid receptor 1platelet-derived growth factor receptorepidermal growth factor receptorsplatelet-derived growth factor receptorssoluble N-ethylmaleimide-sensitive factor attachment protein receptorPeroxisome proliferator-activated receptor δ
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Authors
Giuseppe Maulucci, Bareket Daniel, Ofir Cohen, Yossef Avrahami, Shlomo Sasson,