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J. Biol. Chem., Vol. 282, Issue 3, 1925-1937, January 19, 2007

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Ethanol-induced Modulation of Hepatocellular Extracellular Signal-regulated Kinase-1/2 Activity via 4-Hydroxynonenal^*

Brante P. Sampey, Benjamin J. Stewart, and Dennis R. Petersen¹

From the Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver and Health Sciences Center, Denver, Colorado 80262 and the Departments of Nutrition, and Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599

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.

Received for publication, November 15, 2006

^* This work was supported by National Institutes of Health Grant AA009300. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmaceutical Sciences, University of Colorado Denver and Health Sciences Center, SOP Rm. 434, Box C238, 4200 East Ninth Ave., Denver, CO 80262. Tel.: 303-315-6159; Fax: 303-315-0274; E-mail: Dennis.Petersen{at}uchsc.edu.

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