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Clin Exp Pharmacol Physiol. 2009 May;36(5-6):463-8. doi: 10.1111/j.1440-1681.2009.05152.x. Epub 2009 Feb 10.

Overexpression of aldehyde dehydrogenase-2 attenuates chronic alcohol exposure-induced apoptosis, change in Akt and Pim signalling in liver.

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1
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming School of Pharmacy, Laramie, WY 82071, USA.

Abstract

1. The liver, the main site of ethanol oxidation, is extremely vulnerable to the toxic effects of alcohol. Chronic alcohol intake has been shown to result in alcoholic liver disease, although the precise mechanism of action remains poorly understood. 2. The present study was designed to examine the impact of facilitated acetaldehyde metabolism via overexpression of aldehyde dehydrogenase-2 (ALDH2) on chronic alcohol ingestion-induced hepatic damage. Mice (wild-type Friend Virus B (FVB) and ALDH2 transgenic mice) were placed on a 4% alcohol or control diet for 12 weeks. Pro- and anti-apoptotic proteins, including p53, Omi/HtrA2, Bcl-2, Bax, X-linked inhibitor of apoptosis protein (XIAP), Akt, phosphorylated (p) Akt, the Akt downstream signalling molecule Pim and pPim, were examined using immunoblot analysis. Apoptosis and protein damage were assessed using the caspase 3 assay and protein carbonyl formation, respectively. 3. The data revealed that alcohol intake enhanced expression of p53, Omi/HtrA2, Bcl-2 and Bax without affecting XIAP expression or the Bcl-2/Bax ratio. Total Akt and pPim were downregulated in response to alcohol, whereas total Pim was upregulated in conjunction with unchanged pAkt. As a result, the pAkt : Akt and pPim : Pim ratios were elevated and reduced, respectively, in response to alcohol. All these effects that resulted from alcohol exposure were attenuated or ablated by ALDH2. 4. Collectively, the results suggest that ALDH2 may effectively ameliorate alcohol-induced hepatic apoptosis and changes in Akt as well as Pim signalling.

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