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) |
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Pages (from-to) | 810-824.e8 |
Journal | Molecular Cell |
Volume | 77 |
Issue number | 4 |
DOIs | |
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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