Inhibition of Nuclear Transport of Perilipin 5

• Published in: The FASEB journal Vol. 36 Suppl 1
• Main Authors: Lewis, Hope N, Tansey, John T
• Format: Journal Article
• Language: English
• Published: United States 01.05.2022
• ISSN: 1530-6860
• DOI: 10.1096/fasebj.2022.36.S1.R4646

Obesity, type II diabetes mellitus, and non-alcoholic fatty liver disease are all conditions related to aberrant lipid storage in the organism. 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. These proteins serve as a substrate of protein kinase A, act as cofactors for lipases, are implicated in lipid trafficking, and have been shown to act as transcriptional coactivators. Perilipin 5 is expressed in tissues including oxidative muscle and fasted liver and has been shown to play important roles in neutral lipid metabolism in these tissues and metabolic states. The mechanism through which perilipin 5 enters the nucleus is not known. Using a cultured cell model expressing either perilipin 5 or a perilipin 5 3X-FLAG fusion protein, assayed with immunoblotting and immunofluorescence microscopy we have observed protein kinase A dependent phosphorylation of perilipin 5 and translocation of perilipin 5 to the cytosol and nucleus. There are five 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 synthetic steroid mifepristone, but not other inhibitors, block entry, implicating the importin α/β1 nuclear transport pathway in this process. These data indicate that the biological function of perilipin 5 can be at least partially blocked pharmacologically using commercially available drugs. This presents an interesting potential for further examination and treatment of metabolic diseases.