Control of drug and ethanol metabolism

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DESCRIPTION (provided by applicant): We have identified a novel potential mechanism by which alcohol causes liver damage. Specifically, we showed that hepatic expression of plasminogen activator inhibitor-1 (PAI-1) is upregulated by ethanol and the level of expression correlates with protection against liver damage in enteral alcohol model. Furthermore, we showed that PAI-1-/- mice are protected against not only fatty liver due to alcohol, but also later stages of the disease (inflammation, necrosis and fibrosis). We therefore hypothesize that PAI-1 upregulation plays a causal role in ALD. We will build on this hypothesis via the following specific aims. 1) Is PAI-1 involved in enteral alcohol-induced liver injury in mice? We will directly test this hypothesis by investigating the effect of inhibition of PAI-1 expression on liver damage due to alcohol in the enteral mouse model. Specific subhypotheses to be tested are: a) Absence of PAI-1 will protect against experimental ALD in mice, b) PAI-1 mediates steatosis after alcohol via impaired VLDL synthesis, c) PAI-1 mediates hepatic inflammation during chronic alcohol exposure via fibrin deposition. 2. To determine the mechanism(s) by which PAI-1 is induced by alcohol. The purpose of this specific aim is to identify the major mechanisms by which PAI-1 is induced by chronic alcohol. Specific subhypotheses to be tested are: a) TNFa is the major inducer of PAI-1 due to ethanol. b) PAI-1 is induced by alcohol via mechanisms involving impaired hepatic insulin signaling. 3) To determine the mechanism(s) by which PAI-1 mediates hepatic fibrosis we will build on Preliminary Studies testing the hypothesis that PAI-1 also plays a causal role in hepatic fibrosis. Specific subhypotheses to be tested are: a) PAI-1-/- mice are protected against hepatic fibrosis at the level of matrix resolution, b) Matrix metalloproteases are required for enhanced matrix resolution in PAI-1-/- mice, c) Inhibition of PAI-1 will enhance recovery from established fibrosis and cirrhosis. Taken together, we expect the results of this work to identify a new causal role of PAI-1 in alcoholic liver injury at the level of early damage (steatosis, inflammation and necrosis), as well as in later stages of the disease (i.e., fibrosis and cirrhosis). We therefore expect that the results of this work will identify targeting PAI-1 as a new potential therapy for ALD.