Background: Chronic liver disease is characterized by extensive fibrosis, necropoptosis and sinusoidal dysfunction. The pancaspase inhibitor emricasan has shown promising results improving liver sinusoidal microvascular dysfunction, fibrosis, and portal hypertension in pre-clinical models of advanced chronic liver disease (Gracia-Sancho et al. AASLD16). Nevertheless, its effects on hepatocyte’s biology have not been adequately studied.
Methodology: We assessed the effects of 24h-emricasan (10-50uM), or vehicle, on the phenotype of primary human hepatocytes isolated from cirrhotic liver explants cultured in an advanced fluidic device that mimics the liver sinusoid. Diclofenac was used as hepatotoxicity positive control.
In addition, we studied the effects of in vivo administration of emricasan on the phenotype and function of primary hepatocytes in cirrhotic rats treated for 7 days with emricasan(10mg/kg/day) or vehicle(carboxymethylcellulose).
Results: Human cirrhotic hepatocytes treated with emricasan exhibited improved phenotype as demonstrated by higher albumin and urea production (+60% & +17%, respectively). Similarly, hepatocytes isolated from emricasan-treated cirrhotic rats showed increased urea production(+160%) and CYP3A4 activity(+101%) suggesting improved synthetic and detoxification capacity. Moreover, hepatocyte phenotype was maintained as evidenced by sustained expression of the master regulator HNF4a(+180%) and the transporters Abcc3(-63%), Slc22a7(+80%), Slc22a1(+250%) and Slc10a1(+170%).
Emricasan showed no hepatotoxicity neither in human nor rat hepatocytes shown as the maintenance of cell viability and normal levels of transaminases and LDH in cell media (in vitro), and improved biochemical tests in treated-rats (in vivo). Conclusions: Emricasan improves the phenotype of cirrhotic hepatocytes without evidence of hepatotoxicity, further encouraging its clinical evaluation for the treatment of chronic liver disease.
