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

Mol Cell. 2020 Feb 20;77(4):810-824.e8. doi: 10.1016/j.molcel.2019.12.003. Epub 2019 Dec 31.


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.

Keywords: ATGL; MUFA; PGC-1α; PLIN5; SIRT1; fatty acids; lipid droplets; lipolysis; olive oil; oxidative metabolism.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Animals
  • Biological Transport
  • Cell Line
  • Cells, Cultured
  • Diet
  • Fatty Acids / metabolism
  • Fatty Acids, Monounsaturated / metabolism*
  • Lipase / metabolism
  • Lipid Droplets / chemistry*
  • Male
  • Mice, Inbred C57BL
  • Olive Oil
  • Perilipin-5 / metabolism*
  • Perilipin-5 / physiology
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Sirtuin 1 / metabolism*
  • Transcription, Genetic


  • Fatty Acids
  • Fatty Acids, Monounsaturated
  • Olive Oil
  • Perilipin-5
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Plin5 protein, mouse
  • Lipase
  • PNPLA2 protein, mouse
  • Sirtuin 1