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

Violeta I. Gallardo-Montejano, Geetu Saxena, Christine M. Kusminski, Chaofeng Yang, John L. McAfee, Lisa Hahner, Kathleen Hoch, William Dubinsky, Vihang A. Narkar and Perry E. Bickel ()
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Violeta I. Gallardo-Montejano: The University of Texas Southwestern Medical Center
Geetu Saxena: Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for The Prevention Of Human Diseases, UT Health
Christine M. Kusminski: Touchstone Diabetes Center, The University of Texas Southwestern Medical Center
Chaofeng Yang: The University of Texas Southwestern Medical Center
John L. McAfee: The University of Texas Southwestern Medical Center
Lisa Hahner: The University of Texas Southwestern Medical Center
Kathleen Hoch: Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for The Prevention Of Human Diseases, UT Health
William Dubinsky: Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for The Prevention Of Human Diseases, UT Health
Vihang A. Narkar: Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for The Prevention Of Human Diseases, UT Health
Perry E. Bickel: The University of Texas Southwestern Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12723

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