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J Biol Chem
2007 Jan 19;2823:1925-37. doi: 10.1074/jbc.M610602200.
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Ethanol-induced modulation of hepatocellular extracellular signal-regulated kinase-1/2 activity via 4-hydroxynonenal.
Sampey BP
,
Stewart BJ
,
Petersen DR
.
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Modulation of the extracellular signal-regulated kinases (ERK-1/2), a signaling pathway directly associated with cell proliferation, survival, and homeostasis, has been implicated in several pathologies, including alcoholic liver disease. However, the underlying mechanism of ethanol-induced ERK-1/2 modulation remains unknown. This investigation explored the effects of ethanol-associated oxidative stress on constitutive hepatic ERK-1/2 activity and assessed the contribution of the lipid peroxidation product 4-hydroxynonenal (4-HNE) to the observations made in vivo. Constitutive ERK-1/2 phosphorylation was suppressed in hepatocytes isolated from rats chronically consuming ethanol for 45 days. This observation was associated with an increase in 4-HNE-ERK monomer adduct concentration and a hepatic cellular and lobular redistribution of ERK-1/2 that correlated with 4-HNE-protein adduct accumulation. Chronic ethanol consumption was also associated with a decrease in hepatocyte nuclear ELK-1 phosphorylation, independent of changes in total nuclear ELK-1 protein. Primary hepatocytes treated with concentrations of 4-HNE consistent with those occurring during oxidative stress displayed a concentration-dependent decrease in constitutive ERK-1/2 phosphorylation, activity, and nuclear localization that negatively correlated with 4-HNE-ERK-1/2 monomer adduct accumulation. These data paralleled the decreased phosphorylation of the downstream kinase ELK-1. Molar ratios of purified ERK-2 to 4-HNE consistent with pathologic ratios found in vivo resulted in protein monomer-adduct formation across a range of concentrations. Collectively, these data demonstrate a novel association between ethanol-induced lipid peroxidation and the inhibition of constitutive ERK-1/2, and suggest an inhibitory mechanism mediated by the lipid peroxidation product 4-hydroxynonenal.
Aroor,
MAP kinase signaling in diverse effects of ethanol.
2004, Pubmed
Aroor,
MAP kinase signaling in diverse effects of ethanol.
2004,
Pubmed
Benedetti,
Effects of diffusible products of peroxidation of rat liver microsomal lipids.
1979,
Pubmed
Benedetti,
Identification of 4-hydroxynonenal as a cytotoxic product originating from the peroxidation of liver microsomal lipids.
1980,
Pubmed
Bruckner,
JNK3 contributes to c-jun induction and apoptosis in 4-hydroxynonenal-treated sympathetic neurons.
2002,
Pubmed
Camandola,
The lipid peroxidation product 4-hydroxy-2,3-nonenal increases AP-1-binding activity through caspase activation in neurons.
2000,
Pubmed
Camandola,
Biogenic 4-hydroxy-2-nonenal activates transcription factor AP-1 but not NF-kappa B in cells of the macrophage lineage.
1997,
Pubmed
Canuto,
Role of aldehyde metabolizing enzymes in mediating effects of aldehyde products of lipid peroxidation in liver cells.
1994,
Pubmed
Carbone,
Inhibition of Hsp72-mediated protein refolding by 4-hydroxy-2-nonenal.
2004,
Pubmed
Carbone,
Cysteine modification by lipid peroxidation products inhibits protein disulfide isomerase.
2005,
Pubmed
Carbone,
Modification of heat shock protein 90 by 4-hydroxynonenal in a rat model of chronic alcoholic liver disease.
2005,
Pubmed
Carbone,
4-Hydroxynonenal regulates 26S proteasomal degradation of alcohol dehydrogenase.
2004,
Pubmed
Chandler,
Acute ethanol inhibits extracellular signal-regulated kinase, protein kinase B, and adenosine 3':5'-cyclic monophosphate response element binding protein activity in an age- and brain region-specific manner.
2005,
Pubmed
Chen,
MAP kinases.
2001,
Pubmed
Chen,
Effects of ethanol on mitogen-activated protein kinase and stress-activated protein kinase cascades in normal and regenerating liver.
1998,
Pubmed
Cobb,
The mitogen-activated protein kinases, ERK1 and ERK2.
1994,
Pubmed
Davis,
In vivo activation and in situ BDNF-stimulated nuclear translocation of mitogen-activated/extracellular signal-regulated protein kinase is inhibited by ethanol in the developing rat hippocampus.
1999,
Pubmed
Doorn,
Covalent modification of amino acid nucleophiles by the lipid peroxidation products 4-hydroxy-2-nonenal and 4-oxo-2-nonenal.
2002,
Pubmed
Duguay,
Inhibition of liver regeneration by chronic alcohol administration.
1982,
Pubmed
Esterbauer,
Studies on the mechanism of formation of 4-hydroxynonenal during microsomal lipid peroxidation.
1986,
Pubmed
Esterbauer,
Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes.
1991,
Pubmed
Grune,
Accumulation of aldehydic lipid peroxidation products during postanoxic reoxygenation of isolated rat hepatocytes.
1993,
Pubmed
Hamilton,
4-Hydroxynonenal mimics ozone-induced modulation of macrophage function ex vivo.
1996,
Pubmed
Hartley,
4-Hydroxynonenal and malondialdehyde hepatic protein adducts in rats treated with carbon tetrachloride: immunochemical detection and lobular localization.
1999,
Pubmed
Hartley,
Co-metabolism of ethanol, ethanol-derived acetaldehyde, and 4-hydroxynonenal in isolated rat hepatocytes.
1997,
Pubmed
Hartley,
Prooxidant-initiated lipid peroxidation in isolated rat hepatocytes: detection of 4-hydroxynonenal- and malondialdehyde-protein adducts.
1997,
Pubmed
Hendrickson,
Ethanol inhibits mitogen activated protein kinase activity and growth of vascular smooth muscle cells in vitro.
1998,
Pubmed
Herbst,
4-Hydroxynonenal induces dysfunction and apoptosis of cultured endothelial cells.
1999,
Pubmed
Iles,
Mechanisms of glutamate cysteine ligase (GCL) induction by 4-hydroxynonenal.
2005,
Pubmed
Iles,
HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells.
2005,
Pubmed
Ishii,
Molecular basis of enzyme inactivation by an endogenous electrophile 4-hydroxy-2-nonenal: identification of modification sites in glyceraldehyde-3-phosphate dehydrogenase.
2003,
Pubmed
Ishii,
Oxidative stress in alcoholic liver injury.
1997,
Pubmed
Jazirehi,
Inhibition of the Raf-MEK1/2-ERK1/2 signaling pathway, Bcl-xL down-regulation, and chemosensitization of non-Hodgkin's lymphoma B cells by Rituximab.
2004,
Pubmed
Ji,
IkappaB kinase, a molecular target for inhibition by 4-hydroxy-2-nonenal.
2001,
Pubmed
Ji,
4-hydroxynonenal induces apoptosis via caspase-3 activation and cytochrome c release.
2001,
Pubmed
Kamimura,
Increased 4-hydroxynonenal levels in experimental alcoholic liver disease: association of lipid peroxidation with liver fibrogenesis.
1992,
Pubmed
Karin,
The regulation of AP-1 activity by mitogen-activated protein kinases.
1995,
Pubmed
Karin,
AP-1 function and regulation.
1997,
Pubmed
Karin,
Control of transcription factors by signal transduction pathways: the beginning of the end.
1992,
Pubmed
Kono,
Ebselen prevents early alcohol-induced liver injury in rats.
2001,
Pubmed
Kruman,
Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis.
1997,
Pubmed
Leonarduzzi,
The lipid peroxidation end product 4-hydroxy-2,3-nonenal up-regulates transforming growth factor beta1 expression in the macrophage lineage: a link between oxidative injury and fibrosclerosis.
1997,
Pubmed
Li,
4-Hydroxynonenal-induced cell death in murine alveolar macrophages.
1996,
Pubmed
Lindros,
A new oral low-carbohydrate alcohol liquid diet producing liver lesions: a preliminary account.
1998,
Pubmed
Liu,
4-hydroxynonenal triggers an epidermal growth factor receptor-linked signal pathway for growth inhibition.
1999,
Pubmed
Liu,
4-hydroxynonenal induces a cellular redox status-related activation of the caspase cascade for apoptotic cell death.
2000,
Pubmed
Luckey,
4-hydroxynonenal decreases interleukin-6 expression and protein production in primary rat Kupffer cells by inhibiting nuclear factor-kappaB activation.
2002,
Pubmed
Luckey,
Mechanism of inhibition of rat liver class 2 ALDH by 4-hydroxynonenal.
1999,
Pubmed
Malecki,
4-Hydroxynonenal induces oxidative stress and death of cultured spinal cord neurons.
2000,
Pubmed
Meagher,
Alcohol-induced generation of lipid peroxidation products in humans.
1999,
Pubmed
Mitchell,
Inhibition of rat hepatic mitochondrial aldehyde dehydrogenase-mediated acetaldehyde oxidation by trans-4-hydroxy-2-nonenal.
1991,
Pubmed
Mooradian,
Malondialdehyde modification of proteins in vitro is enhanced in the presence of acetaldehyde.
2001,
Pubmed
Niemelä,
Sequential acetaldehyde production, lipid peroxidation, and fibrogenesis in micropig model of alcohol-induced liver disease.
1995,
Pubmed
Niemelä,
Distribution of ethanol-induced protein adducts in vivo: relationship to tissue injury.
2001,
Pubmed
Nordmann,
Ethanol-induced lipid peroxidation and oxidative stress in extrahepatic tissues.
1990,
Pubmed
Ohya,
Reaction of malondialdehyde with deoxyribonucleosides in the presence of acetaldehyde.
1994,
Pubmed
Okada,
4-Hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress. Identification of proteasomes as target molecules.
1999,
Pubmed
Page,
4-Hydroxynonenal prevents NF-kappaB activation and tumor necrosis factor expression by inhibiting IkappaB phosphorylation and subsequent proteolysis.
1999,
Pubmed
Paradis,
In situ detection of lipid peroxidation by-products in chronic liver diseases.
1997,
Pubmed
Paradis,
In situ detection of lipid peroxidation in chronic hepatitis C: correlation with pathological features.
1997,
Pubmed
Parola,
HNE interacts directly with JNK isoforms in human hepatic stellate cells.
1998,
Pubmed
Pearson,
Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions.
2001,
Pubmed
Poli,
Separation and characterization of the aldehydic products of lipid peroxidation stimulated by carbon tetrachloride or ADP-iron in isolated rat hepatocytes and rat liver microsomal suspensions.
1985,
Pubmed
Poli,
4-Hydroxynonenal in the pathomechanisms of oxidative stress.
2000,
Pubmed
Ronis,
Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition.
2005,
Pubmed
Ruef,
Induction of rat aortic smooth muscle cell growth by the lipid peroxidation product 4-hydroxy-2-nonenal.
1998,
Pubmed
Sampey,
Immunohistochemical characterization of hepatic malondialdehyde and 4-hydroxynonenal modified proteins during early stages of ethanol-induced liver injury.
2003,
Pubmed
Teare,
Lipid peroxidation in rats chronically fed ethanol.
1994,
Pubmed
Tjalkens,
Alpha,beta-unsaturated aldehydes increase glutathione S-transferase mRNA and protein: correlation with activation of the antioxidant response element.
1998,
Pubmed
Tsukamoto,
Experimental liver cirrhosis induced by alcohol and iron.
1995,
Pubmed
Tuma,
Role of malondialdehyde-acetaldehyde adducts in liver injury.
2002,
Pubmed
Tyagi,
Grape seed extract inhibits EGF-induced and constitutively active mitogenic signaling but activates JNK in human prostate carcinoma DU145 cells: possible role in antiproliferation and apoptosis.
2003,
Pubmed
Uchida,
Covalent attachment of 4-hydroxynonenal to glyceraldehyde-3-phosphate dehydrogenase. A possible involvement of intra- and intermolecular cross-linking reaction.
1993,
Pubmed
Wands,
Inhibition of hepatic regeneration in rats by acute and chronic ethanol intoxication.
1979,
Pubmed
Watanabe,
Lipid peroxidation product 4-hydroxy-2-nonenal acts synergistically with serotonin in inducing vascular smooth muscle cell proliferation.
2001,
Pubmed
Weng,
Effects of chronic ethanol treatment on the angiotensin II-mediated p42/p44 mitogen-activated protein kinase and phosphorylase a activation in rat hepatocytes.
2003,
Pubmed
Zarkovic,
Stimulation of HeLa cell growth by physiological concentrations of 4-hydroxynonenal.
1993,
Pubmed
de la M Hall,
Models of alcoholic liver disease in rodents: a critical evaluation.
2001,
Pubmed
