Serial Review: 4-Hydroxynonenal as a Signaling MoleculeRegulation of 4-hydroxynonenal-mediated signaling by glutathione S-transferases☆
Introduction
4-Hydroxynonenal (HNE), the most abundant 4-hydroxyalkenal formed in cells, is a toxic end product of lipid peroxidation contributing to the deleterious effects of oxidative stress, and it has been shown to be involved in the pathogenesis of a number of degenerative diseases such as Alzheimer's disease [1], [2], atherosclerosis [3], [4], cataract [5], and cancer [6], [7]. Since the pioneering work of Esterbauer and his associates in the discovery of HNE, studies by his group and various other investigators have demonstrated that HNE can cause apoptosis, cause differentiation, modulate cell growth, and affect various signal transduction pathways (see reviews [8], [9], [10], [11], [12], [13], [14], [15], [16]). Some of these studies suggest that HNE can differentially affect cell cycle signaling events in a concentration-dependent manner [17], [18], [19], implying that the regulation of its intracellular concentrations may be crucial for cells. The mechanisms of this concentration-dependent effect of HNE are not known and difficulty in manipulation of its intracellular concentration poses a problem in studies designed to elucidate these mechanisms.
Within cells, most HNE is generated through uncontrolled nonenzymatic reactions during lipid peroxidation and its homeostasis seems to be regulated primarily by its metabolism. In recent years, there has been a great deal of interest in enzymes responsible for the metabolism and disposition of HNE primarily because of its role in signaling mechanisms. Although a small portion of cellular HNE can be reduced to its corresponding alcohol by alcohol dehydrogenase and aldose reductase, or oxidized to acid by aldehyde dehydrogenase, the majority of HNE is metabolized via its conjugation to glutathione (GSH) through reactions catalyzed by glutathione S-transferases (GSTs) [20], [21]. The resulting conjugate of GSH and HNE (GS-HNE) can be further metabolized to mercapturic acid [22], or the aldehyde group of GS-HNE can be reduced to alcohol by aldose reductase [22], resulting in the formation of the corresponding alcohol. However, our recent studies with human erythrocytes and cell lines suggest that the majority of GS-HNE is transported as such, into the extracellular environment through an ATP-dependent process catalyzed by RLIP76 [23], [24], [25]. Ongoing studies in our laboratory have focused primarily on the role of GSTs in metabolism and detoxification of HNE. In this article, we review some of our recent studies suggesting that GSTs can modulate stress-mediated signaling by regulating the intracellular concentrations of HNE.
Section snippets
Role of HNE in signaling
The evidence for an important role for HNE in signal transduction is provided through studies using several different approaches. In the majority of these studies, the effect of HNE on cells has been studied by directly adding HNE to the media of cell cultures. In general, these studies have shown that moderately high concentrations of HNE can induce apoptosis [17], [23], [26], [27], [28], [29], induce differentiation [12], [17], and affect signaling pathways including activation of adenylate
GSTs: relevance to signaling
As an offshoot of our intensive interest in the studies on structure and function of GSTs and their pharmacological relevance to chemical carcinogenesis, chemoprevention, and the mechanisms of multidrug resistance, we have also studied possible physiological roles of GSTs as antioxidant enzymes [30], [34], [35], [36] because of their Se-independent glutathione peroxidase (GPx) activity [37], [38]. These studies suggest an important role for GSTs in the regulation of HNE homeostasis and cell
GSTs regulate intracellular concentrations of HNE
HNE is formed primarily from the degradation of ω-3 and ω-6 polyunsaturated fatty acids. GSTs can regulate intracellular levels of HNE by attenuating its formation through their GPx activity and also by conjugating it to GSH through their transferase activity. In mammalian tissues, a subgroup of Alpha class GST isozymes has high activity for conjugating HNE to GSH. Table 2 lists major Alpha class GST isozymes whose role in the regulation of intracellular levels of HNE has been established.
Modulation of stress-induced apoptosis by GSTs
Current studies in our laboratory are based on the hypothesis that signaling for apoptosis induced by HNE, or other agents such as H2O2, UV exposure, and xenobiotics, which induce apoptosis and also cause lipid peroxidation (hence a rise in HNE levels), can be modulated by altering GST expression. Results of these studies discussed below are, in general, supportive of this hypothesis and demonstrate that HNE is involved in signaling mechanisms, that at least a part of stress-mediated signaling
HNE-metabolizing GST isozymes can modulate stress-mediated signaling
Recent studies in our laboratory using two separate approaches have demonstrated that HNE-metabolizing GST isozymes can modulate HNE as well as stress-mediated signaling. We have shown that HNE-induced signaling for apoptosis in K562 and HL-60 cells can be blocked by stably transfecting these cells with mGSTA4-4 [17], [29]. Likewise, induction of HNE-metabolizing GSTs provides protection against not only HNE but also stress-mediated apoptosis. These studies further suggest that GSTs are
Depletion of HNE leads to transformation of adherent cells
One of the most striking pieces of evidence supporting the role of HNE as a signaling molecule is provided by our recent studies showing that adherent cells transfected with HNE-metabolizing GSTs undergo transformation and proliferate indefinitely in an anchorage-independent manner [52]. These studies show for the first time that incorporation of HNE-metabolizing GST isozyme hGSTA4-4 in adherent cell lines HLE-B3 and CCL-75, either by cDNA transfection or by microinjection of active enzyme,
Future directions
Studies highlighted in this review strongly suggest that HNE not only is involved in stress-mediated apoptosis but also can affect cell-cycle signaling events in a concentration-dependent manner. It is important to note that only a small increase (about 50%) in HNE levels triggers the activation of JNK upon UVA or heat exposure [23], [28]. Conversely, an only about 50% decrease in HNE levels in mGSTA4-transfected K562 or HL-60 cells causes the cells to proliferate [17], [29]. Attached cells,
Acknowledgements
This work was supported in part by NIH Grants EY 04396 (Y.C.A.), ES 12171 (Y.C.A.), and CA77495 (S.A.) and NIEHS Training Grant ES 007254 (B.P.).
References (72)
- et al.
Glutathione-S-transferase A4-4 modulates oxidative stress in endothelium: possible role in human atherosclerosis
Atherosclerosis
(2004) - et al.
Curcumin protects against 4-hydroxy-2-trans-nonenal-induced cataract formation in rat lenses
Am. J. Clin. Nutr.
(1996) - et al.
Effect of oxidative stress by iron on 4-hydroxynonenal formation and proliferative activity in hepatomas of different degrees of differentiation
Free Radic. Biol. Med.
(1997) - et al.
Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes
Free Radic. Biol. Med.
(1991) - et al.
Induction of differentiation in human HL-60 cells by 4-hydroxynonenal, a product of lipid peroxidation
Exp. Cell Res.
(1991) - et al.
Mutual dependence of growth modifying effects of 4-hydroxynonenal and fetal calf serum in vitro
Free Radic. Biol. Med.
(1994) - et al.
4-Hydroxynonenal modifies the effects of serum growth factors on the expression of the c-fos proto-oncogene and the proliferation of HeLa carcinoma cells
Free Radic. Biol. Med.
(1998) - et al.
Effects of mGST A4 transfection on 4-hydroxynonenal-mediated apoptosis and differentiation of K562 human erythroleukemia cells
Arch. Biochem. Biophys.
(1999) - et al.
Metabolism of the lipid peroxidation product, 4-hydroxy-trans-2-nonenal, in isolated perfused rat heart
J. Biol. Chem.
(1998) - et al.
The hepatocellular metabolism of 4-hydroxynonenal by alcohol dehydrogenase, aldehyde dehydrogenase, and glutathione S-transferase
Arch. Biochem. Biophys.
(1995)
Accelerated metabolism and exclusion of 4-hydroxynonenal through induction of RLIP76 and hGST5.8 is an early adaptive response of cells to heat and oxidative stress
J. Biol. Chem.
Cells preconditioned with mild, transient UVA irradiation acquire resistance to oxidative stress and UVA-induced apoptosis: role of 4-hydroxynonenal in UVA mediated signaling for apoptosis
J. Biol. Chem.
Transfection of mGSTA4 in HL-60 cells protects against 4-hydroxynonenal-induced apoptosis by inhibiting JNK-mediated signaling
Arch. Biochem. Biophys.
Role of glutathione S-transferases in protection against lipid peroxidation: overexpression of hGSTA2-2 in K562 cells protects against hydrogen peroxide induced apoptosis and inhibits JNK and caspase 3 activation
J. Biol. Chem.
Aldose reductase mediates mitogenic signaling in vascular smooth muscle cells
J. Biol. Chem.
The role of human glutathione S-transferases hGSTA1-1 and hGSTA2-2 in protection against oxidative stress
Arch. Biochem. Biophys.
Two distinct 4-hydroxynonenal metabolizing glutathione S-transferase isozymes are differentially expressed in human tissues
Biochem. Biophys. Res. Commun.
Glutathione S-transferases of human lung: characterization and evaluation of the protective role of the alpha-class isozymes against lipid peroxidation
Arch. Biochem. Biophys.
Glutathione peroxidase, an erythrocyte enzyme which protects hemoglobin from oxidative breakdown
J. Biol. Chem.
Role of alpha class glutathione S-transferases as antioxidant enzymes in rodent tissues
Toxicol. Appl. Pharmacol.
4-Hydroxyalk-2-enals are substrates for glutathione transferase
FEBS Lett.
A novel glutathione S-transferase isozyme similar to GST 8-8 of rat and mGSTA4-4 (GST 5.7) of mouse is selectively expressed in human tissues
Biochim. Biophys. Acta
Identification of a novel human glutathione S-transferase using bioinformatics
Arch. Biochem. Biophys.
Physiological role of mGSTA4-4, a glutathione S-transferase metabolizing 4-hydroxynonenal: generation and analysis of mGsta4 null mouse
Toxicol. Appl. Pharmacol.
Role of ultraviolet A-induced oxidative DNA damage in apoptosis via loss of mitochondrial membrane potential and caspase-3 activation
Biochem. Biophys. Res. Commun.
4-Hydroxynonenal-induced MEL cell differentiation involves PKC activity translocation
Biochem. Biophys. Res. Commun.
4-Hydroxynonenal affects pRb/E2F pathway in HL-60 human leukemic cells
Biochem. Biophys. Res. Commun.
Covalent modifications of aminophospholipids by 4-hydroxynonenal
Free Radic. Biol. Med.
Involvement of caspases in 4-hydroxy-alkenal-induced apoptosis in human leukemic cells
Free Radic. Biol. Med.
4-Hydroxynonenal and transforming growth factor-beta1 expression in colon cancer
Mol. Aspects Med.
4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer's disease
J. Neurochem.
Immunohistochemical detection of 4-hydroxy-2-nonenal adducts in Alzheimer's disease is associated with inheritance of APOE4
Am. J. Pathol.
Michael addition-type 4-hydroxy-2-nonenal adducts in modified low-density lipoproteins: markers for atherosclerosis
Biochemistry
Inhibition of melanoma B16-F10 growth by lipid peroxidation product 4-hydroxynonenal
Cancer Biother.
4-Hydroxynonenal from pathology to physiology
Mol. Aspects Med.
Lipid peroxidation and cell cycle signaling: 4-hydroxynonenal, a key molecule in stress mediated signaling
Acta Biochim. Pol.
Cited by (207)
Potential role of Bcl2 in lipid metabolism and synaptic dysfunction of age-related hearing loss
2023, Neurobiology of DiseaseSuppression of uric acid generation and blockade of glutathione dysregulation by L-arginine ameliorates dichlorvos-induced oxidative hepatorenal damage in rats
2021, Biomedicine and PharmacotherapyCitation Excerpt :Therefore, the observation in the present study of a rise in hepatic and renal MDA levels suggests that dichlorvos exposure leads to a rise in hepatorenal MDA levels which could inhibit mitochondrial enzymes like cytochrome c oxidase, oxidizes cardiolipin, impairs mitochondrial respiration, and suppresses mitochondrial biogenesis via reduction of PPAR-γ coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcriptional factor A mRNA [43]. Besides, the increased hepatic and renal lipid peroxidation could be an indication of cell death [42]. Accompanying MDA accumulation, the present study also observed elevated uric and reduced GSH as well as repressed activities of SOD, catalase, and GPx in the hepatic and renal tissues of dichlorvos-exposed animals.
Activating p53 function by targeting RLIP
2021, Biochimica et Biophysica Acta - Reviews on CancerCochlear detoxification: Role of alpha class glutathione transferases in protection against oxidative lipid damage, ototoxicity, and cochlear aging
2021, Hearing ResearchCitation Excerpt :Up to today, ∼20 mammalian GSTs have been identified (Laborde, 2010; McLaren and Moroi, 2003; Simic et al., 2009). The alpha-class GSTs consist of 5 distinct members, GSTA1, GSTA2, GSTA3, GSTA4, and GSTA5 (Awasthi et al., 2004; Balogh and Atkins, 2011; Henderson and Wolf, 2011; Simic et al., 2009; Singh et al., 2010). Of these, GSTA1, GSTA2, GSTA4, and GSTA5 are thought to be the major determinants of the intracellular concentration of 4-HNE, one of the most abundant cytotoxic end products of lipid peroxidation and which contributes to neurodegenerative diseases and age-related diseases (Awasthi et al., 2004; Dalleau et al., 2013; Di Domenico, Tramutola and Butterfield, 2017; Jaganjac et al., 2019; Singhal et al., 2015).
Metabolic regulations in lettuce root under combined exposure to perfluorooctanoic acid and perfluorooctane sulfonate in hydroponic media
2020, Science of the Total EnvironmentEffects of graphene oxide nanomaterial exposures on the marine bivalve, Crassostrea virginica
2019, Aquatic Toxicology
- ☆
This article is part of a series of reviews on “4-Hydroxynonenal as a Signaling Molecule.” The full list of papers may be found on the home page of the journal.