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

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.

Figure 1

Schematic representation of the role of PAI-1 in fibrin(ogen) metabolism in vivo. Cross-linked fibrin deposition is initiated by activation of the coagulation cascade via thrombin. Plasminogen activator inhibitor-1 (PAI-1) inhibits the activity of the plasminogen activators (urokinase-type plasminogen activator [uPA] and tissue-type plasminogen activator [tPA], blocking the activation of plasminogen to plasmin and thereby blunting degradation of fibrin matrices (fibrinolysis). The balance between fibrin deposition and degradation determines whether fibrin accumulates in vivo.

Figure 2

Photomicrographs of livers following chronic ethanol treatment: role of plasminogen activator inhibitor-1 (PAI-1). Representative photomicrographs (original magnification, 100×) of livers from wild-type and PAI-1^-/- mice fed control or ethanol-containing diet for 4 weeks are shown. Higher magnification (200×; lower panels), shows inflammation and necrosis in wild-type mice fed ethanol-containing diet.

Figure 3

Working hypothesis on the mechanism by which plasminogen activator inhibitor-1 (PAI-1) causes hepatic steatosis. In addition to inhibiting fibrinolysis (see Fig. 1), inhibition of urokinase-type plasminogen activator (uPA) prevents the cleavage/maturation of pro-hepatocyte growth factor (HGF). Decreased HGF signaling via the c-Met/ERK pathway leads to a decrease in the expression of apolipoprotein B (Apo) and microsomal triglyceride transfer protein (MTTP) in the cell. The net effect is a decreased assembly and secretion of lipoproteins, resulting in an intracellular triglyceride accumulation. Knocking out PAI-1 or blocking its induction (with metformin) prevents this effect on very low-density lipoprotein (VLDL) production.

Figure 4

Proposed mechanisms by which plasminogen activator inhibitor-1 (PAI-1) inhibition protects against hepatic fibrosis. PAI-1 is a potent inhibitor of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), which convert plasminogen to plasmin. Plasmin can directly degrade extracellular matrix (ECM) components (e.g. fibrin, fibronectin, laminin, proteoglycan, and type IV collagen). Plasmin can also indirectly degrade ECM via activation of matrix metalloprotease (MMP) (e.g. MMP-3).