Review ArticleSignaling properties of 4-hydroxyalkenals formed by lipid peroxidation in diabetes
Graphical abstract
Introduction
Type 2 diabetes mellitus (T2DM) is a chronic disease that has recently reached an epidemic proportion worldwide. Three major stages in the development and progression of the disease have been identified: the first “prediabetes” asymptomatic phase commences with progressive peripheral insulin resistance, impaired glucose tolerance, and subsequently a gradual increase in blood glucose level, which remain below the diabetic threshold due to a compensatory augmented insulin secretion from pancreatic β-cells [1]. Following this overstimulation period, the second phase is characterized by β-cell dysfunction and decompensation that leads to hypoinsulinemia and frank hyperglycemia. At this phase, some peripheral tissues react to the hyperglycemic environment by initiating compensatory defense mechanisms that limit or slow the development of diabetic complications. For instance, skeletal muscles and vascular endothelial and smooth muscle cells reduce the rate of glucose influx by downregulating the expression of their glucose transporters and their abundance in the plasma membrane [2], [3], [4]. In the late stages of T2DM, the chronic nutrient overload (hyperglycemia and/or hyperlipidemia) promotes the secretion of metabolites and factors from adipose depots (adipokines), the liver (hepatokines), and skeletal muscles (myokines) that interfere with these protective mechanisms and cause a progressive damage to peripheral tissues and organs, culminating in cardiovascular disease, nephropathy, neuropathy, or impaired wound healing [5], [6], [7]. Beta-cell apoptosis and death that results in a severe decrease in β-cell mass in islets of Langerhans is also common in the advanced stage of the disease. While these detrimental interactions in the late stages of diabetes have been well characterized and extensively investigated, less is known about the molecular mechanisms underlying the adaptive responses in the early stages. Both peripheral diabetic complications and β-cell failure are associated with an increased production of ROS [8], [9]. Among many direct interactions with macromolecules in cells, ROS also induce nonenzymatic peroxidation of polyunsaturated fatty acids (PUFA) to generate α,β-unsaturated aldehydes that belong to the 4-hydroxyalkenal family (e.g., 4-hydroxy-2E-nonenal; 4-HNE, 4-hydroxy-2E,6Z-dodecadienal; 4-HDDE) [9], [10], [11]. These electrophilic aldehydes avidly bind covalently to nucleophilic moieties in macromolecules and compromise cell functions and structures [12], [13]. Nonetheless, at low and noncytotoxic levels, these aldehydes can function as signaling molecules by interacting with transduction pathways and receptors and thereby promote compensatory defense mechanisms. In many respects these advanced lipid peroxidation products are similar to advanced glycation end products (AGEs) that can evoke cellular regulatory mechanisms by interacting with specific cell surface receptors (RAGEs), whereas their excessive generation and accumulation following chronic hyperglycemia are detrimental to cells and tissues and contribute further to the development of diabetic complications [8], [9], [14], [15], [16], [17]. This review presents recent studies on the dual function of 4-hydroxyalkenals in β-cells and vascular endothelial cells (VEC), where they function as hormetic factors in the prediabetes phase and become cytotoxic agents as the disease progresses.
Section snippets
Compensatory mechanisms and cell decompensation in the progression of T2DM
Hyperglycemia in diabetes results from a combination of peripheral insulin resistance and progressive deterioration of the pancreatic β-cell mass and function, resulting in reduced insulin secretion and circulating levels of the hormone that fail to support adequate metabolism in peripheral insulin-sensitive tissues. Diabetes is also characterized by the development of end-organ complications [18]. The underlying risk factor in the etiology of these complications is hyperglycemia, which alters
PUFA metabolism and peroxidation in diabetes
Arachidonic acid (AA) is a conditionally essential fatty acid available to mammals directly from the diet and/or through enzymatic elongation and desaturation of the essential linoleic acid (LA) [39]. The combined action of fatty acyl-CoA synthase and lysophospholipid acyltransferase promotes the incorporation of AA and LA at the sn-2 position of phospholipids [40], whereas enzymes of the phospholipase A2 (PLA2) family hydrolyze this bond to liberate them. Free AA and LA are transformed to
Cellular targets for 4-hydroxyalkenals
It has been repeatedly shown that exogenous 4-HNE alters vital functions and signaling pathways in cells by covalent interactions with key proteins in signal transduction and regulatory pathways [36], [37], [51], [74], [75], [76], [77], [78], [79], [80]. Among these, 4-HNE affects p38 mitogen-activated protein kinases (p38MAPK) [81], c-Jun N-terminal kinase (JNK) [82], protein kinase Cβ and -δ (PKCβ and PKCδ) [83], [84], cell cycle regulators [85], epithelial growth factor receptor (EGRF) [86],
Role of 4-hydroxyalkenals in VEC and β-cells adaptation to hyperglycemia
As noted above, the rate of 4-HDDE and 4-HNE production in VEC and β-cells, respectively, increases in a glucose-dependent manner. We hypothesized that this phenomenon was primarily due to an increased availability of free AA and LA to peroxidation processes. To investigate this, we performed lipidomic analyses of the composition of the fatty acids in membrane phospholipids of both types of cells following incubation with increasing glucose concentrations. Table 1 shows that abundance of AA and
Are 4-hydroxynonenals involved in VEC and β-cells dysfunction in T2DM?
Similar to other cells [37], in vitro exposure of VEC, INS-1E cells, and freshly isolated rat islets to high and supraphysiological levels of 4-HDDE or 4-HNE induces apoptosis and cell death [9], [30], [31], [138]. This is due primarily to covalent adduct formation with macromolecules and failure of the cellular enzymatic and nonenzymatic neutralization systems to cope with the 4-hydroxyalkenal overload. Some studies on different types of cells and tissues suggest that endogenous 4-HNE may
Conclusions
Lipid peroxidation is enhanced under hyperglycemic conditions and leads to the generation of 4-hydroxyalkenals, such as 4-HNE and 4-HDDE. The tendency of these bioactive aldehydes to form adducts with proteins, phospholipids, and nucleic acid has long been linked to their cytotoxic activities. Indeed, in vitro treatments of VEC and β-cells with these agents induced marked apoptosis and cell death. However, the endogenous levels of 4-HDDE in VEC and of 4-HNE in β-cells under high glucose
Acknowledgments
The study was supported by a grants from the Israel Science Foundation (44/10), the Brettler Center for Research of Molecular Pharmacology and Therapeutics in the Hebrew University and by COST (European Cooperation in Science and Technology) Action CM1201 on “Biomimetic Radical Chemistry.” S. Sasson is the Adolf D. and Horty Storch Chair in Pharmaceutical Sciences, at the Faculty of Medicine, The Hebrew University of Jerusalem, Israel. He is affiliated with the David R. Bloom Center for
References (144)
- et al.
Selective cyclooxygenase-2 inhibitors stimulate glucose transport in L6 myotubes in a protein kinase Cdelta-dependent manner
Biochem. Pharmacol
(2007) - et al.
The diverse ligand repertoire of the receptor for advanced glycation endproducts and pathways to the complications of diabetes
Vasc. Pharmacol.
(2012) - et al.
Blockade of receptor for advanced glycation end-products restores effective wound healing in diabetic mice
Am. J. Pathol.
(2001) - et al.
Eicosanoids, beta-cell function, and diabetes
Prostaglandins Other Lipid Mediat.
(2011) - et al.
Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes
Free Radic. Biol. Med.
(1991) - et al.
Lipidomics of oxidized polyunsaturated fatty acids
Free Radic. Biol. Med.
(2013) - et al.
Acyl-CoA:lysophospholipid acyltransferases
J. Biol. Chem.
(2009) - et al.
Thematic review series: proteomics. An integrated omics analysis of eicosanoid biology
J. Lipid Res.
(2009) - et al.
Human thioredoxin reductase directly reduces lipid hydroperoxides by NADPH and selenocystine strongly stimulates the reaction via catalytically generated selenols
J. Biol. Chem.
(1995) Polyunsaturated fatty acids and inflammatory processes: new twists in an old tale
Biochimie
(2009)