Inhibition of Nuclear Transport of Perilipin 5

Obesity, type II diabetes mellitus, and non-alcoholic fatty liver disease are all conditions related to aberrant lipid storage in humans. Nearly all cells have the capacity to store neutral lipids in lipid storage droplets, organelles that regulate the storage of their hydrophobic contents. All lipid storage droplets are coated with at least one member of the perilipin family of proteins. Perilipin 5 is expressed in oxidative tissues including oxidative muscleand fasted liver and has been shown to play important roles in neutral lipid metabolism in these tissues. Perilipin 5’s involvement in gene expression was discovered during catecholamine-stimulated lipolysis, where the protein is phosphorylated by PKA and forms transcriptional complexes with peroxisome proliferator-activated receptor-gamma coactivator alpha (PGC-1α) and Sirtuin 1 (SIRT1) in the nucleus. Perilipin 5 cannot diffuse through the nuclear membrane because proteins larger than 45 kD must be transported through the nuclear porevia a nuclear pore translocation mechanism. The mechanism through which perilipin 5 enters the nucleus is unknown. There are several known mechanisms for large molecules to gain entry to the nucleus through the nuclear pore. We have used multiple compounds to attempt to block entry of perilipin 5. Preliminary results indicate that the steroid Mifepristone and the anthelmintic Ivermectin block entry, implicating the importin α/ β1 nuclear transport pathway in this process. These data indicate that the function of perilipin 5 can be partially blocked pharmacologically using commercially available drugs. This presents an interesting potential for further examination and treatment of metabolic diseases