title: Protease-activated receptor 1 and hematopoietic cell tissue factor are required for hepatic steatosis in mice fed a Western diet.
abstract: Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome and contributes to increased risk of cardiovascular disease and liver-related morbidity and mortality. Indeed, obese patients with metabolic syndrome generate greater amounts of thrombin, an indication of coagulation cascade activation. However, the role of the coagulation cascade in Western diet-induced NAFLD has not been investigated. Using an established mouse model of Western diet-induced NAFLD, we tested whether the thrombin receptor protease-activated receptor 1 (PAR-1) and hematopoietic cell-derived tissue factor (TF) contribute to hepatic steatosis. In association with hepatic steatosis, plasma thrombin-antithrombin levels and hepatic fibrin deposition increased significantly in C57Bl/6J mice fed a Western diet for 3 months. PAR-1 deficiency reduced hepatic inflammation, particularly monocyte chemoattractant protein-1 expression and macrophage accumulation. In addition, PAR-1 deficiency was associated with reduced steatosis in mice fed a Western diet, including reduced liver triglyceride accumulation and CD36 expression. Similar to PAR-1 deficiency, hematopoietic cell TF deficiency was associated with reduced inflammation and reduced steatosis in livers of low-density lipoprotein receptor-deficient mice fed a Western diet. Moreover, hematopoietic cell TF deficiency reduced hepatic fibrin deposition. These studies indicate that PAR-1 and hematopoietic cell TF are required for liver inflammation and steatosis in mice fed a Western diet.
authors: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors: Karen M
authors: KM
authors: Kassel
authors: A Phillip
authors: AP
authors: Owens
authors: Cheryl E
authors: CE
authors: Rockwell
authors: Bradley P
authors: BP
authors: Sullivan
authors: Ruipeng
authors: R
authors: Wang
authors: Ossama
authors: O
authors: Tawfik
authors: Guodong
authors: G
authors: Li
authors: Grace L
authors: GL
authors: Guo
authors: Nigel
authors: N
authors: Mackman
authors: James P
authors: JP
authors: Luyendyk
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000502:physiology*; D016026:Bone Marrow Transplantation; D004032:Diet / Q000009:adverse effects*; D005234:Fatty Liver / Q000097:blood / Q000209:etiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006505:Hepatitis / Q000503:physiopathology; D050155:Lipogenesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D012333:RNA, Messenger / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000172:deficiency*; D015398:Signal Transduction; D013925:Thromboplastin / Q000172:deficiency*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015430:Weight Gain / Q000502:physiology
chemical_list: D012333:RNA, Messenger; D044463:Receptor, PAR-1; D014409:Tumor Necrosis Factor-alpha; D013925:Thromboplastin