Title: Alcoholic liver disease and the potential role of plasminogen activator inhibitor-1 and fibrin metabolism.

Authors: Beier, Juliane I; Arteel, Gavin E

Published In Exp Biol Med (Maywood), (2012 Jan)

Abstract: Plasminogen activator inhibitor-1 (PAI-1) is a major player in fibrinolysis due to its classical role of inhibiting plasminogen activators. Although increased fibrinolysis is common in alcoholic cirrhosis, decreased fibrinolysis (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 early ALD was unclear. Recent studies in experimental models have suggested that PAI-1 may contribute to the development of early (steatosis), intermediate (steatohepatitis) and late (fibrosis) stages of ALD. For example, fatty liver owing to both acute and chronic ethanol was blunted by the genetic inhibition of PAI-1. This effect of targeting PAI-1 appears to be mediated, at least in part, by an increase in very low-density lipoprotein (VLDL) synthesis in the genetic absence of this acute phase protein. Results from a two-hit model employing ethanol and lipopolysaccharide administration suggest that PAI-1 plays a critical role in hepatic inflammation, most likely due to its ability to cause fibrin accumulation, which subsequently sensitizes the liver to ensuing damaging insults. Lastly, the role of PAI-1 in hepatic fibrosis is less clear and appears that PAI-1 may serve a dual role in this pathological change, both protective (enhancing regeneration) and damaging (blocking matrix degradation). In summary, results from these studies suggest that PAI-1 may play multiple roles in the various stages of ALD, both protective and damaging. The latter effect is mediated by its influence on steatosis (i.e. decreasing VLDL synthesis), inflammation (i.e. impairing fibrinolysis) and fibrosis (i.e. blunting matrix degradation), whereas the former is mediated by maintaining hepatocyte division after an injury.

PubMed ID: 22238286

MeSH Terms: Animals; Disease Progression; Ethanol/pharmacology; Fatty Liver/metabolism; Fatty Liver/pathology; Fibrin/metabolism*; Fibrinolysis; Humans; Lipopolysaccharides/pharmacology; Lipoproteins, VLDL/biosynthesis; Liver Cirrhosis, Alcoholic/metabolism; Liver Cirrhosis, Alcoholic/pathology; Liver Diseases, Alcoholic/metabolism*; Liver Diseases, Alcoholic/pathology; Liver/immunology; Liver/metabolism; Liver/pathology; Mice; Plasminogen Activator Inhibitor 1/metabolism*