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Free Radic Biol Med. 2013 Dec;65:978-987. doi: 10.1016/j.freeradbiomed.2013.08.163. Epub 2013 Aug 20.

Signaling properties of 4-hydroxyalkenals formed by lipid peroxidation in diabetes.

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Department of Pharmacology, Institute for Drug Research, Faculty of Medicine, The Hebrew University, Jerusalem Israel.
Lipinutragen srl, Lipidomic Laboratory, Consiglio Nazionale delle Ricerche, Bologna, Italy.
ISOF, Consiglio Nazionale delle Ricerche, Bologna, Italy.
Endocrinology & Metabolism Service, The Hebrew University-Hadassah Faculty of Medicine, Jerusalem, Israel.
Department of Pharmacology, Institute for Drug Research, Faculty of Medicine, The Hebrew University, Jerusalem Israel. Electronic address:


Peroxidation of polyunsaturated fatty acids is intensified in cells subjected to oxidative stress and results in the generation of various bioactive compounds, of which 4-hydroxyalkenals are prominent. During the progression of type 2 diabetes mellitus, the ensuing hyperglycemia promotes the generation of reactive oxygen species (ROS) that contribute to the development of diabetic complications. It has been suggested that ROS-induced lipid peroxidation and the resulting 4-hydroxyalkenals markedly contribute to the development and progression of these pathologies. Recent findings, however, also suggest that noncytotoxic levels of 4-hydroxyalkenals play important signaling functions in the early phase of diabetes and act as hormetic factors to induce adaptive and protective responses in cells, enabling them to function in the hyperglycemic milieu. Our studies and others' have proposed such regulatory functions for 4-hydroxynonenal and 4-hydroxydodecadienal in insulin secreting β-cells and vascular endothelial cells, respectively. This review presents and discusses the mechanisms regulating the generation of 4-hydroxyalkenals under high glucose conditions and the molecular interactions underlying the reciprocal transition from hormetic to cytotoxic agents.


4-HDDE; 4-HHE; 4-HNE; 4-hydroxy-2E, 6Z-dodecadienal; 4-hydroxy-2E-hexenal; 4-hydroxy-2E-nonenal; 4-hydroxyalkenals; AA; COX; Diabetes; EET; FALDH; GLUT1; GSIS; HETE; HFD; HODE; Hormesis; HpETE; HpODE; LA; LO; Lipid peroxidation; PLA(2); PUFA; Phospholipid remodeling; ROS; T2DM; VEC; Vascular endothelial cells; arachidonic acid; cyclooxygenase; epoxyeicosatrienoic acid; fatty aldehyde dehydrogenase; glucose transporter 1, GPx, glutathione peroxidase; glucose-stimulated insulin secretion; high fat diet; hydroperoxyeicosatetraenoic acid; hydroperoxyoctadecadienoic acid; hydroxyeicosatetraenoic acid; hydroxyoctadecadienoic acid; linoleic acid; lipoxygenase; phospholipase A2; polyunsaturated fatty acids; reactive oxygen species; type 2 diabetes mellitus; vascular endothelial cells.; β-cells

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