Abstract
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-1α. We report that during catecholamine-stimulated lipolysis, Perilipin 5 is phosphorylated by protein kinase A and forms transcriptional complexes with PGC-1α and SIRT1 in the nucleus. Perilipin 5 promotes PGC-1α 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.
Highlights
Dysfunctional cellular lipid metabolism contributes to common chronic human diseases, including type 2 diabetes, obesity, fatty liver disease and diabetic cardiomyopathy
These results are consistent with the gain-of-function studies referenced above and confirm that Perilipin 5 has an important role in regulating cellular lipid metabolism
How do cells in oxidative tissues take full advantage of the liberated free fatty acids by fully catabolizing them to produce ATP or heat and avoid the accumulation of incompletely oxidized lipid species that would damage mitochondria? In this work, we demonstrate a mechanism whereby nuclear Perilipin 5/proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) actions globally reprogram lipid metabolism in response to extracellular signals
Summary
Dysfunctional cellular lipid metabolism contributes to common chronic human diseases, including type 2 diabetes, obesity, fatty liver disease and diabetic cardiomyopathy. Consistent with its tissue distribution, Perilipin 5 gain-of-function in cells increases gene expression of enzymes involved in oxidative catabolism and promotes both triacylglycerol (TAG) storage and fatty acid oxidation[12]. In accord with these in vitro findings, Perilipin 5 skeletal muscle protein positively correlates with both TAG content and palmitate oxidation[16]. As reported we demonstrate that during catecholamine-stimulated lipolysis Perilipin 5 enriches in the nucleus, forms transcriptional complexes with PGC-1a and SIRT1, and promotes the PGC-1a gene program, thereby identifying Perilipin 5 as a previously unrecognized transcriptional co-regulator that helps match mitochondrial capacity to the lipid load
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