From the Cover: Coagulation-Driven Hepatic Fibrosis Requires Protease Activated Receptor-1 (PAR-1) in a Mouse Model of TCDD-Elicited Steatohepatitis.
Emerging evidence supports a role for environmental chemical exposure in the pathology of non-alcoholic fatty liver disease (NAFLD), a disease process tightly linked to increased activity of the blood coagulation cascade. Exposure of C57BL/6 mice to the persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) recapitulates features of the NAFLD spectrum, including steatosis, hepatic injury, inflammation, and fibrosis. We assessed coagulation cascade activation, and determined the role of the thrombin receptor protease activated receptor-1 (PAR-1) in experimental TCDD-elicited NAFLD. Chronic exposure to TCDD (30 µg/kg every 4 days for 28 days) was associated with intrahepatic coagulation, indicated by increased plasma thrombin-antithrombin levels and hepatic fibrin(ogen) deposition. PAR-1 deficiency diminished TCDD-elicited body weight loss and relative liver weight was reduced in TCDD-exposed PAR-1-/-mice compared with TCDD-exposed wild-type mice. PAR-1 deficiency did not affect TCDD-induced hepatic steatosis or hepatocellular injury, as indicated by serum alanine aminotransferase activity. Despite a lack of effect on these 2 features of NAFLD pathology, PAR-1 deficiency was associated with a reduction in hepatic inflammation evident in liver histopathology, and reflected by a reduction in serum levels of the proinflammatory cytokine interleukin-6. Moreover, TCDD-driven hepatic collagen deposition was markedly reduced in PAR-1-deficient mice. These results indicate that experimental TCDD-elicited steatohepatitis is associated with coagulation cascade activation and PAR-1-driven hepatic inflammation and fibrosis.
Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, Michigan.|Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan.
Rance
R
Nault
Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, Michigan.|Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan.
Kelly A
KA
Fader
Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan.|Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
Anna K
AK
Kopec
Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
Jack R
JR
Harkema
Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, Michigan.|Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan.
Timothy R
TR
Zacharewski
Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan; luyendyk@cvm.msu.edu.|Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan.
James P
JP
Luyendyk
D000818:Animals; D001777:Blood Coagulation; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000097:blood; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000072317:Polychlorinated Dibenzodioxins; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D016207:Cytokines; D018836:Inflammation Mediators; D000072317:Polychlorinated Dibenzodioxins; D044463:Receptor, PAR-1; D003094:Collagen
Coagulation; Fibrosis; NAFLD.; PAR-1; TCDD