Background: Signaling through thrombin receptor, protease-activated receptor 1 (PAR1), induces activation of platelets, endothelial cells, and immune cells. High PAR1 expression has been found in non-alcoholic steatohepatitis (NASH). NASH and adipose tissue inflammation are important mediators of cardiovascular disease development in patients with metabolic syndrome.

Aims: To test effects of the direct PAR1-inhibitor vorapaxar on liver injury and adipose tissue inflammation in metabolic syndrome.

Methods and results: Apolipoprotein E knockout (ApoEko) mice fed a high fat diet for 16 weeks (n=6) develop NASH and adipose tissue inflammation. Adding vorapaxar (10mg/kg of western diet) (n=6) reduced circulating markers of liver injury at least by 10% (ALT, AST, GGT, AP, GLDH; p<0.05). In line with this evidence, direct PAR1-inhibition resulted in diminished number of infiltrating, inflammatory cells in liver tissue (CD68⁺ cells, CD3⁺ cells; p<0.05). The transcription of inflammatory mediators (TNF-α, IL-6, IL-1β) was also found to be decreased. Vorapaxar treatment was associated with an 8% reduction in apoptosis (cleaved-caspase 3) in liver tissue. Furthermore, vorapaxar led to a reduction of the transcription of inflammation associated cytokines and chemokines in adipose tissue of ApoEko mice. The number of inflammatory macrophages dropped in adipose tissue by adding vorapaxar to the high fat diet. Above this, markers of liver injury and adipose tissue inflammation positively correlated with the extent of atherosclerotic lesion size, cardiac fibrosis, and thrombogenicity in ApoEko mice (r>0.9, p<0.05).

Conclusion: The direct PAR1-inhibtor vorapaxar possess pleiotropic effects, thereby reducing NASH and adipose tissue inflammation that are both related to cardiovascular disease development.