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
  • 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: [email protected].
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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