Activation of hepatic stellate cells by the ubiquitin C-terminal hydrolase 1 protein secreted from hepatitis C virus-infected hepatocytes

Hepatitis C virus (HCV) infection of hepatocytes promotes liver fibrosis by activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix in liver tissue. Whether or not host factors released from the HCV-infected hepatocytes play role in HSCs activation is unclear. In this study, HSCs were activated by the conditioned medium derived from HCV replicon cells. Secretomic profiling of HCV replicon cells and the parental Huh7 cells revealed ubiquitin carboxy-terminal hydrolase L1 (UCHL1) as a novel secreted protein from HCV-infected hepatocytes. UCHL1 expression in hepatocytes was induced by HCV infection. UCHL1 was expressed in the liver and found in the plasma of patients with chronic hepatitis C. Molecular analysis by use of the anti-UCHL1 neutralization antibody and purified UCHL1 protein showed that secreted UCHL1 protein was bound to the cell surface of HSCs and activated JNK signaling leading to overexpression of alpha-smooth muscle actin and the activation of HSCs. These results provide further for understanding the underlying mechanism in HCV-mediated hepatic fibrogenesis.