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

doi:10.1016/j.molcel.2019.12.003

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 journal › Article › peer-review

123 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 language	English (US)
Pages (from-to)	810-824.e8
Journal	Molecular Cell
Volume	77
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2019.12.003
State	Published - Feb 20 2020

Bibliographical note

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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10.1016/j.molcel.2019.12.003

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Najt, C. P., Khan, S. A., Heden, T. D., Witthuhn, B. A., Perez, M., Heier, J. L., Mead, L. E., Franklin, M. P., Karanja, K. K., Graham, M. J., Mashek, M. T., Bernlohr, D. A., Parker, L., Chow, L. S., & Mashek, D. G. (2020). Lipid Droplet-Derived Monounsaturated Fatty Acids Traffic via PLIN5 to Allosterically Activate SIRT1. Molecular Cell, 77(4), 810-824.e8. https://doi.org/10.1016/j.molcel.2019.12.003

Najt, CP, Khan, SA, Heden, TD, Witthuhn, BA, Perez, M, Heier, JL, Mead, LE, Franklin, MP, Karanja, KK, Graham, MJ, Mashek, MT , Bernlohr, DA , Parker, L , Chow, LS & Mashek, DG 2020, 'Lipid Droplet-Derived Monounsaturated Fatty Acids Traffic via PLIN5 to Allosterically Activate SIRT1', Molecular Cell, vol. 77, no. 4, pp. 810-824.e8. https://doi.org/10.1016/j.molcel.2019.12.003

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title = "Lipid Droplet-Derived Monounsaturated Fatty Acids Traffic via PLIN5 to Allosterically Activate SIRT1",

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, 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",

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

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

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doi = "10.1016/j.molcel.2019.12.003",

language = "English (US)",

volume = "77",

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T1 - Lipid Droplet-Derived Monounsaturated Fatty Acids Traffic via PLIN5 to Allosterically Activate SIRT1

AU - Najt, Charles P.

AU - Khan, Salmaan A.

AU - Heden, Timothy D.

AU - Witthuhn, Bruce A.

AU - Perez, Minervo

AU - Heier, Jason L.

AU - Mead, Linnea E.

AU - Franklin, Mallory P.

AU - Karanja, Kenneth K.

AU - Graham, Mark J.

AU - Mashek, Mara T.

AU - Bernlohr, David A.

AU - Parker, Laurie

AU - Chow, Lisa S.

AU - Mashek, Douglas G.

PY - 2020/2/20

Y1 - 2020/2/20

N2 - 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.

AB - 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.

KW - ATGL

KW - fatty acids

KW - lipid droplets

KW - lipolysis

KW - MUFA

KW - olive oil

KW - oxidative metabolism

KW - PGC-1α

KW - PLIN5

KW - SIRT1

KW - Allosteric Regulation

KW - Fatty Acids, Monounsaturated/metabolism

KW - Male

KW - Olive Oil

KW - Perilipin-5/metabolism

KW - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism

KW - Biological Transport

KW - Transcription, Genetic

KW - Lipid Droplets/chemistry

KW - Cell Line

KW - Fatty Acids/metabolism

KW - Mice, Inbred C57BL

KW - Cells, Cultured

KW - Animals

KW - Diet

KW - Lipase/metabolism

KW - Sirtuin 1/metabolism

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UR - http://www.scopus.com/inward/citedby.url?scp=85079374939&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2019.12.003

DO - 10.1016/j.molcel.2019.12.003

M3 - Article

C2 - 31901447

AN - SCOPUS:85079374939

SN - 1097-2765

VL - 77

SP - 810-824.e8

JO - Molecular Cell

JF - Molecular Cell

IS - 4

ER -

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

Abstract

Bibliographical note

Keywords

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

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

Publisher link

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Nikon A1RSI Confocal with SIM Super Resolution

University Imaging Centers

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