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

47 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)810-824.e8
JournalMolecular Cell
Volume77
Issue number4
DOIs
StatePublished - Feb 20 2020

Bibliographical note

Funding Information:
We would like to thank Candace Guerrero, Mitchell Fuller, Michael Autry, Colleen Forster, and Guillermo Marques for their technical assistance. We thank the University of Minnesota Imaging Center, Center for Mass Spectrometry and Proteomics, Clinical and Translational Science Biospecimen Support Center, and the Biophysical Technology Center for providing instrumentation and expertise. We thank Eduarado Chini for help with initial SIRT1 assays, Barbara Atshaves for antibodies and protocols, and Ann Hertzel for scientific discussions. Funding was provided for C.P.N. (NIH: T32DK007203 and T32AG029796), T.D.H. (NIH: F32DK109556 and L30DK110338), M.P. (NIH: R01CA182543-S1), M.P.F. (NIH: T32DK083250), D.A.B. (NIH: R01DK053189 and the University of Minnesota E-0917-2), L.S.C. (NIH: R01DK098203), and D.G.M. (NIH: R01AG055452, R01DK108790, R01DK114401, and the American Diabetes Association: 1-16-IBS-203). D.G.M. C.P.N. T.D.H. L.S.C. and S.A.K. conception and design of research; C.P.N. T.D.H. S.A.K. M.P. J.L.H. L.E.M. M.P.K. K.K.K. and M.T.M. performed experiments; C.P.N. T.D.H. S.A.K. D.G.M. and B.A.W. analyzed data; C.P.N. T.D.H. L.S.C. D.A.B. and D.G.M. interpreted results of experiments; C.P.N. S.A.K. and D.G.M. prepared figures; C.P.N. and D.G.M. drafted manuscript; M.J.G. J.L.H. and L.P. contributed materials and regents necessary for completion of studies; C.P.N. D.G.M. D.A.B. L.S.C. T.D.H. and B.A.W. edited and revised manuscript; C.P.N. S.A.K. T.D.H. B.A.W. M.P. J.L.H, L.E.M. M.P.F. K.K.K. M.J.G. M.T.M. D.A.B. L.P. L.S.C. and D.G.M. approved final version of manuscript. The authors declare no competing interests.

Funding Information:
We would like to thank Candace Guerrero, Mitchell Fuller, Michael Autry, Colleen Forster, and Guillermo Marques for their technical assistance. We thank the University of Minnesota Imaging Center, Center for Mass Spectrometry and Proteomics, Clinical and Translational Science Biospecimen Support Center, and the Biophysical Technology Center for providing instrumentation and expertise. We thank Eduarado Chini for help with initial SIRT1 assays, Barbara Atshaves for antibodies and protocols, and Ann Hertzel for scientific discussions. Funding was provided for C.P.N. ( NIH : T32DK007203 and T32AG029796 ), T.D.H. ( NIH : F32DK109556 and L30DK110338 ), M.P. ( NIH : R01CA182543-S1 ), M.P.F. ( NIH : T32DK083250 ), D.A.B. ( NIH : R01DK053189 and the University of Minnesota E-0917-2 ), L.S.C. ( NIH : R01DK098203 ), and D.G.M. ( NIH : R01AG055452 , R01DK108790 , R01DK114401 , and the American Diabetes Association : 1-16-IBS-203 ).

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • 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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