Coagulation cascade activation and protease activated receptor‐1 contribute to hepatic steatosis in a mouse model of diet‐induced obesity

Non‐alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and the metabolic syndrome and contributes to cardiovascular disease and liver‐related morbidity. Thrombin generation is increased in patients with obesity and metabolic syndrome. However, the role of the coagulation cascade in NAFLD has not been investigated. Using LDLr −/− mice fed a Western Diet, a mouse model of diet‐induced obesity, we tested the hypothesis that hematopoietic cell‐derived tissue factor and the thrombin receptor protease activated receptor‐1 (PAR‐1) contribute to steatosis in mice. In association with hepatic steatosis, plasma thrombin‐antithrombin (TAT) levels increased in LDLr −/− mice fed a Western diet. Hematopoietic cell TF deficiency reduced fibrin deposition and steatosis in livers of LDLr −/− mice fed a Western diet. Liver triglyceride accumulation and steatosis were reduced in PAR‐1 −/− mice fed a Western diet. TF deficiency and PAR‐1 deficiency reduced hepatic expression of the proinflammatory genes TNFα and MCP‐1 and the lipogenic genes SCD1 and CD36. The results indicate that hematopoietic cell TF and PAR‐1 activation contribute to liver steatosis in a mouse model of diet‐induced obesity. Financial support: AHA 0835121G, NIH R01 ES017537 , and P20 RR021940.