2. Academic Validation
  3. Lipid Droplet-Derived Monounsaturated Fatty Acids Traffic via PLIN5 to Allosterically Activate SIRT1

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.
Charles P Najt 1,  Salmaan A Khan 1,  Timothy D Heden 1,  Bruce A Witthuhn 1,  Minervo Perez 1,  Jason L Heier 1,  Linnea E Mead 1,  Mallory P Franklin 2,  Kenneth K Karanja 1,  Mark J Graham 3,  Mara T Mashek 1,  David A Bernlohr 1,  Laurie Parker 1,  Lisa S Chow 4,  Douglas G Mashek 5
Affiliations

Affiliations

  • 1 Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
  • 2 Department of Food Science and Nutrition, University of Minnesota, Minneapolis, MN, USA.
  • 3 Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA.
  • 4 Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA.
  • 5 Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA; Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA. Electronic address: dmashek@umn.edu.
PMID: 31901447 DOI: 10.1016/j.molcel.2019.12.003
Abstract

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.

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