title: Nuclear Perilipin 5 integrates lipid droplet lipolysis with PGC-1α/SIRT1-dependent transcriptional regulation of mitochondrial function.
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.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Violeta I
authors.initials: VI
authors.lastname: Gallardo-Montejano
authors.affiliation: Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for The Prevention Of Human Diseases, UT Health, Houston, Texas 77030, USA.
authors.forename: Geetu
authors.initials: G
authors.lastname: Saxena
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Kusminski
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Yang
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: John L
authors.identifier: 0000-0001-7645-631X
authors.initials: JL
authors.lastname: McAfee
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Hahner
authors.affiliation: Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for The Prevention Of Human Diseases, UT Health, Houston, Texas 77030, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Hoch
authors.affiliation: Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for The Prevention Of Human Diseases, UT Health, Houston, Texas 77030, USA.
authors.forename: William
authors.initials: W
authors.lastname: Dubinsky
authors.affiliation: Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for The Prevention Of Human Diseases, UT Health, Houston, Texas 77030, USA.
authors.forename: Vihang A
authors.initials: VA
authors.lastname: Narkar
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Perry E
authors.identifier: 0000-0001-6018-9579
authors.initials: PE
authors.lastname: Bickel
mesh_terms: D052437:Adipocytes, Brown / Q000378:metabolism; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D066292:Lipid Droplets / Q000378:metabolism; D008066:Lipolysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D002395:Catecholamines; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C551268:lipid storage droplet protein 5, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1