New role of plasminogen activator inhibitor‐1 in alcohol‐induced liver injury

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Abstract
Plasminogen activator inhibitor‐1 (PAI‐1) is the main inhibitor of plasminogen activators, thereby playing a major role in fibrinolysis. Whereas hyperfibrinolysis is common in alcoholic cirrhosis, hypofibrinolysis (driven mostly by elevated levels of PAI‐1) is common during the development of alcoholic liver disease (ALD). However, whether or not PAI‐1 plays a causal role in the development of ALD has been unclear. The role of PAI‐1 was therefore investigated in models of early (steatosis), intermediate (inflammation/necrosis) and late (fibrosis) stages of alcoholic liver disease. For example, hepatic steatosis caused by both acute and chronic ethanol was blunted by inhibiting PAI‐1 activation. This effect of inhibiting PAI‐1 appears to be mediated, at least in part, by an increase in very low‐density lipoprotein (VLDL) synthesis in the absence of PAI‐1. The results from that study also indicated that PAI‐1 plays a critical role in both acute and chronic hepatic inflammation. Lastly, knocking out PAI‐1 potently protected against experimental hepatic fibrosis; the mechanism of this protective effect appears to be mediated predominantly by extracellular matrix (ECM) resolution by matrix metalloproteases, which are indirectly inhibited by PAI‐1. In summary, targeting PAI‐1 protects against all three stages of ALD in model systems. The mechanisms by which PAI‐1 contributes to these disease stages appear to not only involve the ‘classical’ function of PAI‐1 (i.e. in mediating fibrinolysis), but also other functions of this protein. These data support a role of PAI‐1 in the initiation and progression of ALD, and suggest that PAI‐1 may be a useful target for clinical therapy to halt or blunt disease progression.

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