In addition to blocking SREBP-mediated up-regulation of hepatic genes during HCV infection, we hypothesized that blocking SKI-1/S1P endoprotease activity would also compromise cellular lipid storage. Analysis of intracellular lipid content and cytoplasmic LD abundance in Spn4A.RRLL(s)-expressing cells confirmed our hypothesis. In addition, we observed a decrease in ADRP/perilipin 2 abundance in Spn4A.RRLL(s)-expressing cells compared to control-treated cells. The physiological role of ADRP has yet to be fully established but it plays an important role in LD structure and formation. Interestingly, ADRP is degraded through the proteasome-dependent pathway during regression of lipidstoring cells, indicating that when ADRP is not bound to LDs, such as in SKI-1/S1P-inhibited cells, it will be susceptible to rapid proteasomal degradation [81] . Clinical studies have demonstrated that there is a correlation between the level of ADRP and the degree of hepatocyte steatogenesis in humans [82] . In addition, ADRP is found to be up-regulated in fatty liver in humans and in mice with liver steatosis [83] . Collectively, these observations suggest that inhibition of SKI-1/S1P offers an attractive therapeutic target for reducing HCV-induced liver steatosis.