title: Tissue factor-deficiency and protease activated receptor-1-deficiency reduce inflammation elicited by diet-induced steatohepatitis in mice.
abstract: Altered hepatic lipid homeostasis, hepatocellular injury, and inflammation are features of nonalcoholic steatohepatitis, which contributes significantly to liver-related morbidity and mortality in the Western population. A collection of inflammatory mediators have been implicated in the pathogenesis of steatohepatitis in mouse models. However, the pathways essential for coordination and amplification of hepatic inflammation and injury caused by steatosis are not completely understood. We tested the hypothesis that tissue factor (TF)-dependent thrombin generation and the thrombin receptor protease activated receptor-1 (PAR-1) contribute to liver inflammation induced by steatosis in mice. Wild-type C57Bl/6J mice fed a diet deficient in methionine and choline for 2 weeks manifested steatohepatitis characterized by increased serum alanine aminotransferase activity, macrovesicular hepatic steatosis, hepatic inflammatory gene expression, and lobular inflammation. Steatohepatitis progression was associated with thrombin generation and hepatic fibrin deposition. Coagulation cascade activation was significantly reduced in low TF mice, which express 1% of normal TF levels. Hepatic triglyceride accumulation was not affected in low TF mice or PAR-1-deficient mice. In contrast, biomarkers of hepatocellular injury, inflammatory gene induction, and hepatic accumulation of macrophages and neutrophils were greatly reduced by TF-deficiency and PAR-1-deficiency. The results suggest that TF-dependent thrombin generation and activation of PAR-1 amplify hepatic inflammation and injury during the pathogenesis of steatohepatitis.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, 3901 Rainbow Blvd, MS-1018, Kansas City, KS 66160, USA. jluyendyk@kumc.edu
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Sullivan
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
authors.forename: Ruipeng
authors.initials: R
authors.lastname: Wang
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001777:Blood Coagulation; D001779:Blood Coagulation Factors / Q000378:metabolism; D018932:Chemokine CCL2 / Q000097:blood; D002794:Choline / Q000378:metabolism; D004032:Diet / Q000009:adverse effects*; D005234:Fatty Liver / Q000097:blood / Q000150:complications* / Q000201:enzymology / Q000473:pathology*; D005786:Gene Expression Regulation; D007249:Inflammation / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D044463:Receptor, PAR-1 / Q000172:deficiency* / Q000378:metabolism; D013917:Thrombin / Q000096:biosynthesis; D013925:Thromboplastin / Q000172:deficiency* / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001779:Blood Coagulation Factors; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D044463:Receptor, PAR-1; D014280:Triglycerides; D013925:Thromboplastin; D008715:Methionine; D000410:Alanine Transaminase; D013917:Thrombin; D002794:Choline