Therapeutic administration of the direct thrombin inhibitor argatroban reduces hepatic inflammation in mice with established fatty liver disease

Am J Pathol. 2012 Oct;181(4):1287-95. doi: 10.1016/j.ajpath.2012.06.011. Epub 2012 Jul 26.

Abstract

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 ∼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 O staining, and hepatic triglyceride levels. Argatroban reduced serum triglyceride and cholesterol levels in mice fed a Western diet. Argatroban reduced both α-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokine CCL2 / metabolism
  • Chemokine CXCL2 / genetics
  • Chemokine CXCL2 / metabolism
  • Collagen / metabolism
  • Diet
  • Fatty Liver / blood
  • Fatty Liver / complications*
  • Fatty Liver / drug therapy*
  • Feeding Behavior / drug effects
  • Gene Expression Regulation / drug effects
  • Inflammation / blood
  • Inflammation / complications
  • Inflammation / drug therapy*
  • Inflammation / pathology
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Lipid Metabolism / drug effects
  • Lipid Metabolism / genetics
  • Lipids / blood
  • Liver / drug effects
  • Liver / pathology
  • Liver Cirrhosis / blood
  • Liver Cirrhosis / complications
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / pathology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Pipecolic Acids / administration & dosage
  • Pipecolic Acids / pharmacology*
  • Pipecolic Acids / therapeutic use*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, LDL / deficiency
  • Receptors, LDL / metabolism
  • Thrombin / antagonists & inhibitors*
  • Thrombin / metabolism
  • Weight Gain / drug effects

Substances

  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Chemokine CXCL2
  • Cxcl2 protein, mouse
  • Lipids
  • Pipecolic Acids
  • RNA, Messenger
  • Receptors, LDL
  • Intercellular Adhesion Molecule-1
  • Collagen
  • Thrombin
  • argatroban