Therapeutic administration of a direct thrombin inhibitor reduces hepatic inflammation in a mouse model of hypercholesterolemia

Abstract

Deficiency in the thrombin receptor protease activated receptor‐1 reduces hepatic inflammation and steatosis in mice fed a Western diet. We tested the hypothesis that thrombin inhibition could reverse hepatic steatosis and inflammation in mice with established diet‐induced fatty liver disease. LDLr−/− mice were fed a control diet or a Western diet for 19 weeks. Mice were given either the direct thrombin inhibitor argatroban or its vehicle for the final 4 weeks. Argatroban administration reduced macrophage and neutrophil accumulation in livers of mice fed a Western diet. Similarly, in mice fed a Western diet, argatroban administration reduced hepatic expression of MCP‐1, ICAM‐1, and MIP‐2, three mediators that can contribute to hepatic macrophage and neutrophil accumulation. In addition, argatroban tended to reduce hepatic steatosis, as indicated by hepatic triglyceride levels. Argatroban completely reversed the increase in serum triglycerides and reduced total serum cholesterol levels in mice fed a Western diet. Argatroban also reduced the expression of profibrogenic genes encoding Type 1 collagen and TIMP‐1 in livers of mice fed a Western diet. Overall, this study indicates that therapeutic intervention with a thrombin inhibitor rapidly reduces several features of diet‐induced NAFLD in mice. This work was supported by AHA Grants 0835121G and 11POST7430043 and by NIH Grants R01 ES017537 and DK073566.