Regulation of heme oxygenase expression by alcohol, hypoxia and oxidative stress.
OBJECTIVE
To study the effect of both acute and chronic alcohol exposure on heme oxygenases (HOs) in the brain, liver and duodenum.


METHODS
Wild-type C57BL/6 mice, heterozygous Sod2 knockout mice, which exhibit attenuated manganese superoxide dismutase activity, and liver-specific ARNT knockout mice were used to investigate the role of alcohol-induced oxidative stress and hypoxia. For acute alcohol exposure, ethanol was administered in the drinking water for 1 wk. Mice were pair-fed with regular or ethanol-containing Lieber De Carli liquid diets for 4 wk for chronic alcohol studies. HO expression was analyzed by real-time quantitative polymerase chain reaction and Western blotting.


RESULTS
Chronic alcohol exposure downregulated HO-1 expression in the brain but upregulated it in the duodenum of wild-type mice. It did not alter liver HO-1 expression, nor HO-2 expression in the brain, liver or duodenum. In contrast, acute alcohol exposure decreased both liver HO-1 and HO-2 expression, and HO-2 expression in the duodenum of wild-type mice. The decrease in liver HO-1 expression was abolished in ARNT(+/-) mice. Sod2(+/-) mice with acute alcohol exposure did not exhibit any changes in liver HO-1 and HO-2 expression or in brain HO-2 expression. However, alcohol inhibited brain HO-1 and duodenal HO-2 but increased duodenal HO-1 expression in Sod2(+/-) mice. Collectively, these findings indicate that acute and chronic alcohol exposure regulates HO expression in a tissue-specific manner. Chronic alcohol exposure alters brain and duodenal, but not liver HO expression. However, acute alcohol exposure inhibits liver HO-1 and HO-2, and also duodenal HO-2 expression.


CONCLUSIONS
The inhibition of liver HO expression by acute alcohol-induced hypoxia may play a role in the early phases of alcoholic liver disease progression.
Lisa Nicole Gerjevic, Sizhao Lu, Jonathan Pascal Chaky, Duygu Dee Harrison-Findik, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5820, United States.
Lisa Nicole
LN
Gerjevic
Sizhao
S
Lu
Jonathan Pascal
JP
Chaky
Duygu Dee
DD
Harrison-Findik