Inhibition of plasminogen suppresses fibrosis and macrophage foaming in a nonalcoholic steatohepatitis mouse model

Abstract

Nonalcoholic steatohepatitis is a clinically important liver disease. Its symptoms are exacerbated by macrophage foaming, which is promoted by plasminogen in vitro. However, the influence of plasminogen on nonalcoholic steatohepatitis has not been reported. In this study, we evaluated the influence of plasminogen in a mouse model of nonalcoholic steatohepatitis with macrophage foaming. L−/−/A−/− mice, characterized by hypercholesterolemia, were injected with streptozotocin and fed a high‐fat diet to develop nonalcoholic steatohepatitis with macrophage foaming. To confirm the influence of plasminogen, we used the well‐known plasminogen inhibitor tranexamic acid and L−/−/A−/−/Plg−/− mice, which are deficient in plasminogen and investigated the influence on nonalcoholic steatohepatitis. The influence of plasminogen on the expression levels of proinflammatory cytokines involved in foaming in macrophages was also assessed. The formation of nonalcoholic steatohepatitis lesions with macrophage foaming was confirmed in the L−/−/A−/− mouse model. Tranexamic acid attenuated foaming and fibrosis in the L−/−/A−/− mice. Similarly, foaming and liver fibrosis were also attenuated in the L−/−/A−/−/Plg−/− mice. The mRNA expression levels of TGF‐β1 and IL‐1β in liver and peritoneal macrophages were reduced upon plasminogen inhibition. We show that inhibition of plasminogen suppressed macrophage foaming, cytokine expression, and consequently fibrosis in nonalcoholic steatohepatitis. Our results provide a clue toward various processes leading to fibrosis and may contribute to new therapeutic strategies for nonalcoholic steatohepatitis.