Nuclear Perilipin 5 integrates lipid droplet lipolysis with PGC-1α/SIRT1-dependent transcriptional regulation of mitochondrial function
| Autor: | Geetu Saxena, Perry E. Bickel, Lisa Hahner, John L. McAfee, Chaofeng Yang, Vihang A. Narkar, Christine M. Kusminski, Kathleen Hoch, Violeta I. Gallardo-Montejano, William P. Dubinsky |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Science Lipolysis General Physics and Astronomy Muscle Proteins Oxidative phosphorylation Mitochondrion Biology Models Biological General Biochemistry Genetics and Molecular Biology Article Myoblasts 03 medical and health sciences Mice Catecholamines Sirtuin 1 Lipid droplet Transcriptional regulation Animals Protein kinase A Promoter Regions Genetic Cell Nucleus Multidisciplinary Intracellular Signaling Peptides and Proteins General Chemistry Lipid Droplets Cyclic AMP-Dependent Protein Kinases Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Cell biology Mitochondria Mice Inbred C57BL 030104 developmental biology Adipocytes Brown Mitochondrial biogenesis Biochemistry Gene Expression Regulation Perilipin Female Deacetylase activity |
| Zdroj: | Nature Communications Nature Communications, Vol 7, Iss 1, Pp 1-14 (2016) |
| ISSN: | 2041-1723 |
| Popis: | 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. Perilipin 5 has been implicated as a modulator of lipase activity and a scaffold linking lipid droplets to mitochondria. Here the authors show that PKA stimulates Peripilin 5 interaction with nuclear PGC-1a and SIRT1 to promote transcription of genes regulating mitochondrial biogenesis and respiration. |
| Databáze: | OpenAIRE |
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