Therapeutic Administration of the Direct Thrombin Inhibitor Argatroban Reduces Hepatic Inflammation in Mice with Established Fatty Liver Disease
Therapeutic Administration of the Direct Thrombin Inhibitor Argatroban Reduces Hepatic Inflammation in Mice with Established Fatty Liver Disease
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DOI：
10.1016/j.ajpath.2012.06.011
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发表时间：
2012-10-01
影响因子：
6
通讯作者：
Luyendyk, James P.
中科院分区：
文献类型：
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作者：
Kassel, Karen M.;Sullivan, Bradley P.;Luyendyk, James P.
非酒精性脂肪性肝病（NAFLD）患者和饮食诱导的肥胖小鼠模型中凝血酶生成增加。凝血酶受体蛋白酶激活受体-1的缺乏减少了喂食西方饮食的小鼠的肝脏炎症和脂肪变性。然而，目前还不清楚凝血酶抑制剂是否可以改变已建立的NAFLD的发病机制。我们测试了凝血酶抑制可以逆转饮食诱导的NAFLD小鼠的肝脏脂肪变性和炎症的假设。低密度脂蛋白受体缺陷型LDLr-/-小鼠喂食对照饮食或西方饮食19周。在研究的最后4周，通过微渗透泵给予小鼠类似于15 mg/kg/天的直接凝血酶抑制剂阿加曲班或其溶媒。阿加曲班给药显著降低了肝脏促炎细胞因子的表达，并减少了喂食西方饮食的小鼠肝脏中巨噬细胞和中性粒细胞的积累。阿加曲班没有显著影响肝脂肪变性，如组织病理学、油红0染色和肝甘油三酯水平所示。阿加曲班降低了喂食西方饮食的小鼠的血清甘油三酯和胆固醇水平。阿加曲班降低了喂食西方饮食的小鼠肝脏中的α-平滑肌肌动蛋白表达和1型胶原mRNA水平，表明肝星状细胞的活化减少。这项研究表明，凝血酶抑制剂的治疗性干预减弱了西方饮食喂养的小鼠的肝脏炎症和几种促纤维化变化。(Am J Pathol 2012，181：1287-1295; http：//dx·doi·org/10·1016/j·ajpath·2012·06·011）
Thrombin generation is increased in patients with nonalcoholic fatty liver disease (NAFLD) and in mouse models of diet-induced obesity. Deficiency in the thrombin receptor protease activated receptor-1 reduces hepatic inflammation and steatosis in mice fed a Western diet. However, it is currently unclear whether thrombin inhibitors can modify the pathogenesis of established NAFLD. We tested the hypothesis that thrombin inhibition could reverse hepatic steatosis and inflammation in mice with established diet-induced NAFLD. Low-density lipoprotein receptor-deficient LDLr-/- mice were fed a control diet or a Western diet for 19 weeks. Mice were given the direct thrombin inhibitor argatroban similar to 15 mg/kg/day or its vehicle via a miniosmotic pump for the final 4 weeks of the study. Argatroban administration significantly reduced hepatic proinflammatory cytokine expression and reduced macrophage and neutrophil accumulation in livers of mice fed a Western diet. Argatroban did not significantly impact hepatic steatosis, as indicated by histopathology, Oil Red 0 staining, and hepatic triglyceride levels. Argatroban reduced serum triglyceride and cholesterol levels in mice fed a Western diet. Argatroban reduced both a-smooth muscle actin expression and Type 1 collagen mRNA levels in livers of mice fed a Western diet, indicating reduced activation of hepatic stellate cells. This study indicates that therapeutic intervention with a thrombin inhibitor attenuates hepatic inflammation and several profibrogenic changes in mice fed a Western diet. (Am J Pathol 2012, 181:1287-1295; http://dx.doi.org/10.1016/j.ajpath.2012.06.011)