Abstract 10107: Tissue Factor Expressed by Hematopoietic Cells is Required for the Development of Non-Alcoholic Fatty Liver Disease in Mice Fed a High Fat Diet.
Non-alcoholic fatty liver disease (NAFLD) is an important feature of the Metabolic Syndrome and contributes significantly to liver-related morbidity in the Western population. In a subset of patients, NAFLD progresses to the more severe non-alcoholic steatohepatitis (NASH), and the mechanism underlying this transition is not clear. We have shown previously in a methionine-choline-deficient diet model of NASH that either low levels of tissue factor (TF) or a complete deficiency of protease activated receptor-1 (PAR-1) reduces liver inflammation. However, the role of the coagulation cascade in models of high fat diet (HFD)-induced NAFLD has not been investigated, and the cell types expressing TF critical for NAFLD progression are not known. We tested the hypothesis that hematopoietic cell TF contributes to the development of NAFLD and NASH in mice. Low density lipoprotein receptor deficient mice (LDLr−/−) mice fed a HFD for 3 months developed macrovesicular steatosis associated with increased expression of inflammatory genes such as TNFα, COX-2, and MCP−1. Plasma thrombin-antithrombin (TAT) levels and hepatic fibrin deposition increased in LDLr−/− mice fed the HFD, indicating coagulation cascade activation. To evaluate the contribution of hematopoietic cell TF to steatosis in this model, we utilized bone marrow transplantation. LDLr−/− mice with TF+/−hTF+ bone marrow fed a HFD developed macrovesicular steatosis in association with hepatic fibrin deposition. In contrast, fibrin deposition and steatosis were significantly reduced in livers of LDLr−/− mice with low TF (TF−/−hTF+) bone marrow. Hepatic expression of the lipogenic genes CD36 and SCD-1 was significantly reduced in LDLr−/− mice with low TF (TF−/−hTF+) bone marrow fed HFD, indicating that TF expressed by hematopoietic cells affects fatty acid uptake and de novo synthesis in the liver. Moreover, hepatic TNFα and MCP-1 mRNA levels were significantly reduced by hematopoietic cell TF-deficiency. The results indicate that hematopoietic cell TF contributes significantly to the development of liver steatosis and inflammation in mice fed a HFD. This novel result highlights an important contribution of extrahepatic cells to the pathogenesis of NAFLD and NASH.
- © 2010 by American Heart Association, Inc.