Nuclear Perilipin 5 integrates lipid droplet lipolysis with PGC-1 alpha/SIRT1-dependent transcriptional regulation of mitochondrial function

作者：Gallardo Montejano Violeta I; Saxena Geetu; Kusminski Christine M; Yang Chaofeng; McAfee John L; Hahner Lisa; Hoch Kathleen; Dubinsky William; Narkar Vihang A; Bickel Perry E^*

来源：Nature Communications, 2016, 7(1): 12723.

DOI：10.1038/ncomms12723

Dysfunctional cellular lipid metabolism contributes to common chronic human diseases, including type 2 diabetes, obesity, fatty liver disease and diabetic cardiomyopathy. How cells balance lipid storage and mitochondrial oxidative capacity is poorly understood. Here we identify the lipid droplet protein Perilipin 5 as a catecholamine-triggered interaction partner of PGC-1 alpha. We report that during catecholamine-stimulated lipolysis, Perilipin 5 is phosphorylated by protein kinase A and forms transcriptional complexes with PGC-1 alpha and SIRT1 in the nucleus. Perilipin 5 promotes PGC-1 alpha co-activator function by disinhibiting SIRT1 deacetylase activity. We show by gain-and-loss of function studies in cells that nuclear Perilipin 5 promotes transcription of genes that mediate mitochondrial biogenesis and oxidative function. We propose that Perilipin 5 is an important molecular link that couples the coordinated catecholamine activation of the PKA pathway and of lipid droplet lipolysis with transcriptional regulation to promote efficient fatty acid catabolism and prevent mitochondrial dysfunction.

• 出版日期2016-8