The mechanisms of liver injury in alcoholic liver disease in rats fed ethanol are numerous. One of these mechanisms involves free radical generation when ethanol is metabolized by CYP2E1 in the liver. The free radicals produced lead to the increase in formation of products of lipid peroxidation including 4 hydroxynonenal (4HNE). 4HNE forms adducts with various proteins including some of the subunits of the 26s proteasome. Chronic ethanol ingestion also induces post translational modification of the proteasomes such as hyperphosphorylation of the subunits. Therefore, we hypothesize that when ethanol is consumed continuously for a prolonged period, CYP2E1 is induced and this generates a free radical attack on lipids. The by- products alter the proteasomal subunits to cause loss of catalytic function. The loss of proteolysis by the proteasome leads to the accumulation of altered proteins in the cells.
Specific Aim 1 : To determine the molecular post translational modifications of the 20s and 19s proteasome subunits from the liver of rats-fed ethanol intragastrically for 1 month (in vivo model). Hypothesis: 4HNE adducts and phosphorylation on specific sites on subunits of the proteasome accounts for the loss of catalytic activity in chronic ethanol fed rats.
Specific Aim 2 : To determine [the molecular mechanisms of proteasome inhibition by alcohol in vitro using the HepG2 CYP2E1 transduced cell line].
Specific Aim 3 : To determine [by microarray analysis, the changes in gene expression associated with ethanol inhibition of the proteasome, comparing the rat fed ethanol in vivo with the HepG2 model in vitro]. If this approach determines [how] ethanol-induces proteasomal inhibition, then a new mechanism of ethanol-induced liver injury will have been established which could provide a target for therapeutic intervention.
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