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

Nat Commun. 2016 Aug 24;7:12723. doi: 10.1038/ncomms12723.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, Brown / metabolism
  • Animals
  • Catecholamines / metabolism
  • Cell Nucleus / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Female
  • Gene Expression Regulation
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lipid Droplets / metabolism
  • Lipolysis*
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Models, Biological
  • Muscle Proteins / antagonists & inhibitors
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Myoblasts / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
  • Promoter Regions, Genetic
  • Sirtuin 1 / metabolism*

Substances

  • Catecholamines
  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • lipid storage droplet protein 5, mouse
  • Cyclic AMP-Dependent Protein Kinases
  • Sirt1 protein, mouse
  • Sirtuin 1