Lipid Droplet-Derived Monounsaturated Fatty Acids Traffic via PLIN5 to Allosterically Activate SIRT1

Charles P. Najt, Salmaan A. Khan, Timothy D. Heden, Bruce A. Witthuhn, Minervo Perez, Jason L. Heier, Linnea E. Mead, Mallory P. Franklin, Kenneth K. Karanja, Mark J. Graham, Mara T. Mashek, David A. Bernlohr, Laurie Parker, Lisa S. Chow, Douglas G. Mashek

Research output: Contribution to journalArticlepeer-review

95 Scopus citations


Lipid droplets (LDs) provide a reservoir for triacylglycerol storage and are a central hub for fatty acid trafficking and signaling in cells. Lipolysis promotes mitochondrial biogenesis and oxidative metabolism via a SIRT1/PGC-1α/PPARα-dependent pathway through an unknown mechanism. Herein, we identify that monounsaturated fatty acids (MUFAs) allosterically activate SIRT1 toward select peptide-substrates such as PGC-1α. MUFAs enhance PGC-1α/PPARα signaling and promote oxidative metabolism in cells and animal models in a SIRT1-dependent manner. Moreover, we characterize the LD protein perilipin 5 (PLIN5), which is known to enhance mitochondrial biogenesis and function, to be a fatty-acid-binding protein that preferentially binds LD-derived monounsaturated fatty acids and traffics them to the nucleus following cAMP/PKA-mediated lipolytic stimulation. Thus, these studies identify the first-known endogenous allosteric modulators of SIRT1 and characterize a LD-nuclear signaling axis that underlies the known metabolic benefits of MUFAs and PLIN5.

Original languageEnglish (US)
Pages (from-to)810-824.e8
JournalMolecular Cell
Issue number4
StatePublished - Feb 20 2020

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Inc.


  • ATGL
  • fatty acids
  • lipid droplets
  • lipolysis
  • MUFA
  • olive oil
  • oxidative metabolism
  • PGC-1α
  • PLIN5
  • SIRT1
  • Allosteric Regulation
  • Fatty Acids, Monounsaturated/metabolism
  • Male
  • Olive Oil
  • Perilipin-5/metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
  • Biological Transport
  • Transcription, Genetic
  • Lipid Droplets/chemistry
  • Cell Line
  • Fatty Acids/metabolism
  • Mice, Inbred C57BL
  • Cells, Cultured
  • Animals
  • Diet
  • Lipase/metabolism
  • Sirtuin 1/metabolism

PubMed: MeSH publication types

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


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