Abstract 18552: The Thrombin Inhibitor Dabigatran Inhibits High Fat Diet-induced Obesity and Fatty Liver Disease in Mice
Inflammation associated with non-alcoholic fatty liver disease (NALFD) increases the risk of adverse cardiovascular events. NAFLD is the hepatic manifestation of obesity and the metabolic syndrome and significantly contributes to liver-related morbidity. We have shown previously that the thrombin receptor protease activated receptor-1 (PAR-1) is essential for hepatic inflammation and steatosis in mice fed a high fat diet (HFD), but PAR-1 deficiency does not affect weight gain in mice fed a HFD. To determine whether pharmacologic inhibitors of thrombin could reduce the progression of NAFLD in mice on a HFD, we utilized the direct thrombin inhibitor, dabigatran etexilate. Wild type C57Bl/6 mice were fed a HFD formulated to contain dabigatran (10 mg/g chow) or an identical HFD with starch substituted for drug for 3 months. Plasma thrombin time was significantly prolonged in mice fed HFD+dabigatran, but no adverse bleeding events were observed. Despite consuming a similar amount of chow, mice fed HFD+dabigatran gained significantly less body weight compared to mice fed HFD alone. Induction of inflammatory genes including TNFα, MCP-1, and the lipogenic genes SCD-1 and CD36, was significantly reduced in livers of mice fed HFD+dabigatran compared to mice fed HFD alone. In agreement, hepatic steatosis was dramatically reduced by dabigatran in mice fed a HFD. In summary, pharmacologic inhibition of thrombin with dabigatran reduced various features of NAFLD in mice fed a HFD. In contrast to PAR-1-deficient mice, dabigatran administration also dramatically reduced diet-induced obesity. Taken together, the results indicate that thrombin contributes to NAFLD in mice fed a HFD, and that thrombin promotes diet-induced obesity in a PAR-1-independent manner. Clinical evaluation of the potential for thrombin inhibition to reduce systemic and hepatic inflammation in obese patients taking dabigatran for another indication, such as atrial fibrillation, could reveal novel beneficial effects of oral thrombin inhibitors in metabolic disease.
- © 2012 by American Heart Association, Inc.