Thrombin Inhibition with Dabigatran Protects against High-Fat Diet–Induced Fatty Liver Disease in Mice
| Autor: | Karen M. Kassel, James P. Luyendyk, Nikita Joshi, Bradley P. Sullivan, Anna K. Kopec, Matthew J. Flick, Keara Towery |
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| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty Gene Expression Diet High-Fat Weight Gain Fibrin Bile Acids and Salts Mice Thrombin Non-alcoholic Fatty Liver Disease Internal medicine Nonalcoholic fatty liver disease medicine Animals Inflammation Pharmacology Liver injury biology business.industry Fatty liver nutritional and metabolic diseases Alanine Transaminase Lipid Metabolism medicine.disease Dabigatran Fatty Liver Mice Inbred C57BL Endocrinology Liver Alanine transaminase Direct thrombin inhibitor beta-Alanine biology.protein Molecular Medicine Benzimidazoles Steatosis business Gastrointestinal Hepatic Pulmonary and Renal medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 351:288-297 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.114.218545 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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