Proteasome inhibitor attenuates the activation of hepatic stellate cell

Abstract

Chronic liver disease progresses to cirrhosis and often develops into hepatocarcinoma. The final stage of the disease is fatal liver failure, and death from liver cancer is common. The development of treatments for chronic liver diseases has been a priority to prevent the progression to cirrhosis and the development of hepatocarcinoma. In fact, there are no approved drugs for nonalcoholic fatty liver disease (NAFLD) which represents the most common cause of chronic liver disease in many countries. It is now well-established that in NAFLD, mortality is highest with advanced fibrosis. Therefore, there is an urgent need to develop therapies that inhibit or ameliorate liver fibrosis. 

Liver fibrosis is common pathological condition of chronic liver diseases caused by scarring due to excessive production and accumulation of extracellular matrix. Hepatic stellate cells, which are activated by liver injury and are a major source of collagen and other extracellular matrix, have attracted attention as a therapeutic target for liver fibrosis. We conducted a drug screening using human-derived hepatic stellate cells and found that several proteasome inhibitors including bortezomib and carfilzomib suppressed the function and proliferation of hepatic stellate cells. Furthermore, a 2^nd generation proteasome inhibitor, carfilzomib also suppressed cell proliferation and decreased the production of extracellular matrix including Collagen and Timp1 in hepatic stellate cells isolated from mouse liver. Currently, CCL4-induced liver fibrosis is being studied by using a mouse model. 

Inhibiting the function and proliferation of hepatic stellate cells with proteasome inhibitors, especially carfilzomib, could potentially suppress and improve liver fibrosis and provide a new treatment widely applicable to chronic liver disease.