A critical function of the SREBP pathway and the genes that it regulates is to control lipid homeostasis [36] . We investigated the impact of inhibiting SKI-1/S1P using both Spn4A.RRLL(s) and PF-429242 on total intracellular lipid levels, specifically cholesterol, cholesterol-esters, triglycerides, and phospholipids ( Figure 3C and 3D). Among the cell lipids examined, Spn4A.RRLL(s) and PF-429242 had the most dramatic impact on cholesterol-ester levels, a major constituent of cellular LDs [5] ; these were reduced by 74% in Spn4A.RRLL(s)-treated cells compared to control (Ad-Empty)-treated cells ( Figure 3C ). Similarly, PF-429242 reduced cholesterol-ester levels by , 63% compared to control cells treated with DMSO ( Figure 3D ). A 14% reduction in triglycerides was also induced by Spn4A.RRLL(s), although this reduction did not reach significance, whereas PF-429242 caused a significant 51% reduction in total intracellular triglycerides. A significant 5% reduction in free cholesterol levels was also observed in Spn4A.RRLL(s)-treated cells and a 25% reduction was observed in PF-429242-treated cells compared to respective controls. No significant reductions in phospholipid levels were detected ( Figure 3C and 3D). These results suggest that sustained inhibition of SKI-1/S1P-mediated cleavage and activation of SREBP causes increased cellular utilization of lipid stores.