Clusterin Attenuates Hepatic Fibrosis by Inhibiting Hepatocyte Apoptosis and Hepatic Stellate Cell Activation

Background: The activation of hepatic stellate cells (HSCs) is a critical initiating process of hepatic fibrosis, and its regulation has not been fully elucidated. Clusterin (CLU) has been implicated in multiple diseases, yet little is known about its expression profile in the liver and its regulatory role in hepatic fibrosis. The aim of this study was to investigate the CLU expression profile in the liver and clarify the effect of CLU on HSCs and hepatic fibrosis. Methods: Murine fibrosis models were established. The expression of CLU was detected at cellular and tissue levels. Mice overexpressing CLU in the liver were generated using AAV vectors. The effect of CLU on hepatocytes and HSCs was explored in vivo and in vitro . Results: CLU was synthesized and secreted by hepatocytes in the liver, and its expression was upregulated during hepatic fibrosis progression. CLU overexpression in mice attenuated liver injury and fibrogenesis. Furthermore, CLU was found to inhibit tumor necrosis factor alpha-induced hepatocyte apoptosis. In addition, secreted CLU decreased the level of HSC activation mediated by transforming growth factor β1/Smad3 signaling. Conclusion: These results revealed that CLU is a protective factor in hepatic fibrosis and exerts synergistic regulatory effects on hepatocytes and HSCs in the fibrotic microenvironment.