title: Thrombin inhibition with dabigatran protects against high-fat diet-induced fatty liver disease in mice.
abstract: Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of obesity and metabolic syndrome. Robust coagulation cascade activation is common in obese patients with NAFLD. We identified a critical temporal relationship between thrombin generation and the manifestation of hepatic steatosis, inflammation, and injury in C57BL/6J mice fed a high-fat diet (HFD) for 1, 2, and 3 months. Mice fed a HFD exhibited dramatic increases in hepatocellular injury and inflammation over time. Hepatic fibrin deposition preceded an increase in serum alanine aminotransferase, and the most dramatic changes in liver histopathology occurred in conjunction with a detectable increase in plasma thrombin-antithrombin levels at 3 months. To directly determine whether thrombin activity promotes NAFLD pathogenesis, mice were fed a HFD and simultaneously treated with the direct thrombin inhibitor dabigatran etexilate for 3 months. Notably, dabigatran treatment significantly reduced hepatic fibrin deposition, hepatic inflammation, hepatocellular injury, and steatosis in mice fed a HFD. Of interest, dabigatran treatment also significantly attenuated HFD-induced body weight gain. Gene expression analysis suggested that thrombin potentially drives NAFLD pathogenesis by altering the expression of genes associated with lipid metabolism and bile acid synthesis. Collectively, the results suggest that thrombin activity is central to HFD-induced body weight gain, liver injury, and inflammation and provide the proof-of-principle evidence that pharmacological thrombin inhibition could be effective in limiting NAFLD and associated pathologies.
authors.affiliation: Department of Pathobiology & Diagnostic Investigation (A.K.K., K.L.T., J.P.L.), Department of Pharmacology & Toxicology (N.J.), Michigan State University, East Lansing, Michigan; Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (K.M.K., B.P.S.); and Cancer and Blood Diseases Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio (M.J.F.).
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kopec
authors.affiliation: Department of Pathobiology & Diagnostic Investigation (A.K.K., K.L.T., J.P.L.), Department of Pharmacology & Toxicology (N.J.), Michigan State University, East Lansing, Michigan; Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (K.M.K., B.P.S.); and Cancer and Blood Diseases Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio (M.J.F.).
authors.forename: Nikita
authors.initials: N
authors.lastname: Joshi
authors.affiliation: Department of Pathobiology & Diagnostic Investigation (A.K.K., K.L.T., J.P.L.), Department of Pharmacology & Toxicology (N.J.), Michigan State University, East Lansing, Michigan; Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (K.M.K., B.P.S.); and Cancer and Blood Diseases Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio (M.J.F.).
authors.forename: Keara L
authors.initials: KL
authors.lastname: Towery
authors.affiliation: Department of Pathobiology & Diagnostic Investigation (A.K.K., K.L.T., J.P.L.), Department of Pharmacology & Toxicology (N.J.), Michigan State University, East Lansing, Michigan; Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (K.M.K., B.P.S.); and Cancer and Blood Diseases Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio (M.J.F.).
authors.forename: Karen M
authors.initials: KM
authors.lastname: Kassel
authors.affiliation: Department of Pathobiology & Diagnostic Investigation (A.K.K., K.L.T., J.P.L.), Department of Pharmacology & Toxicology (N.J.), Michigan State University, East Lansing, Michigan; Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (K.M.K., B.P.S.); and Cancer and Blood Diseases Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio (M.J.F.).
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Sullivan
authors.affiliation: Department of Pathobiology & Diagnostic Investigation (A.K.K., K.L.T., J.P.L.), Department of Pharmacology & Toxicology (N.J.), Michigan State University, East Lansing, Michigan; Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (K.M.K., B.P.S.); and Cancer and Blood Diseases Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio (M.J.F.).
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Flick
authors.affiliation: Department of Pathobiology & Diagnostic Investigation (A.K.K., K.L.T., J.P.L.), Department of Pharmacology & Toxicology (N.J.), Michigan State University, East Lansing, Michigan; Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (K.M.K., B.P.S.); and Cancer and Blood Diseases Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio (M.J.F.) luyendyk@cvm.msu.edu.
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000096:biosynthesis; D000069604:Dabigatran; D059305:Diet, High-Fat / Q000009:adverse effects*; D005234:Fatty Liver / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005337:Fibrin; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015430:Weight Gain / Q000187:drug effects; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D001647:Bile Acids and Salts; D015091:beta-Alanine; D005337:Fibrin; D000410:Alanine Transaminase; D013917:Thrombin; D000069604:Dabigatran