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. ? ? ?

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Gentry, Thomas
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University of Louisville
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Beier, Juliane I; Guo, Luping; Ritzenthaler, Jeffrey D et al. (2016)  Fibrin-mediated integrin signaling plays a critical role in hepatic regeneration after partial hepatectomy in mice. Ann Hepatol 15:762-72
Ding, Xiang; Beier, Juliane I; Baldauf, Keegan J et al. (2014) Acute ethanol preexposure promotes liver regeneration after partial hepatectomy in mice by activating ALDH2. Am J Physiol Gastrointest Liver Physiol 306:G37-47
Kaiser, J Phillip; Guo, Luping; Beier, Juliane I et al. (2014) PKCε contributes to chronic ethanol-induced steatosis in mice but not inflammation and necrosis. Alcohol Clin Exp Res 38:801-9
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Beier, Juliane I; Arteel, Gavin E (2012) Alcoholic liver disease and the potential role of plasminogen activator inhibitor-1 and fibrin metabolism. Exp Biol Med (Maywood) 237:1-9

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