Dataset Information

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.

SUBMITTER: Najt CP

PROVIDER: S-EPMC7036014 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Najt Charles P CP Khan Salmaan A SA Heden Timothy D TD Witthuhn Bruce A BA Perez Minervo M Heier Jason L JL Mead Linnea E LE Franklin Mallory P MP Karanja Kenneth K KK Graham Mark J MJ Mashek Mara T MT Bernlohr David A DA Parker Laurie L Chow Lisa S LS Mashek Douglas G DG

Molecular cell 20191231 4

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 cel ...[more]

PMID: 31901447

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Project description:Obesity is a recognized epidemic worldwide, and the accumulation of excess free saturated fatty acids (SFAs) in cells induces cellular lipotoxic damage and increases the risk of a wide spectrum of metabolic diseases including type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) have been reported to combat SFA-induced cellular damage. However, the comparative studies of the two types of unsaturated fatty acids (UFAs) are still limited. We investigated the effects of different MUFAs and PUFAs in the human hepatocyte line L-02 cells in vitro, and in high-fat-diet (HFD)-induced obese C57BL/6 mice in vivo. The results of the in vitro study showed that SFAs induced significant cellular lipotoxic damage, but the combination of MUFAs/PUFAs with SFAs significantly improved the impaired cell viability. Particularly, oleic acid (OA) was superior to eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA), and arachidonic acid (AA) in terms of its anti-apoptotic effect and inhibition of endoplasmic reticulum (ER) stress. In vivo, both olive-oil-enriched (HFD + OO) and fish-oil-enriched high-fat diets (HFD + FO) reduced hepatic steatosis and improved insulin sensitivity in obese mice. However, FO induced an abnormal increase in serum aspartate aminotransferase (AST) and an increase in the oxidative stress indicator Malondialdehyde (MDA). Liver-targeted lipidomic analysis showed that liver lipid metabolites under the two types of UFA dietary interventions differed from the HFD group, modulating the abundance of some lipid metabolites such as triglycerides (TGs) and glycerophospholipids. Furthermore, the FO diet significantly increased the abundance of the associated FA 20:5 long-chain lipid metabolites, whereas the OO diet regulated the unsaturation of all fatty acids in general and increased the abundance of FA 18:1 in the overall lipid metabolites, especially TGs, which may primarily contribute to the FO, and OO drove protection in NAFLD.

Project description:BackgroundMonounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) have been reported to combat saturated fatty acid (SFA)-induced cellular damage, however, their clinical effects on patients with metabolic diseases such as diabetes and hyperlipidemia are still controversial. Since comparative studies of the effects of these two types of unsaturated fatty acids (UFAs) are still limited. In this study, we aimed to compare the protective effects of various UFAs on pancreatic islets under the stress of SFA-induced metabolic disorder and lipotoxicity.MethodsRat insulinoma cell line INS-1E were treated with palmitic acid (PA) with or without UFAs including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and oleic acid (OA) to determine cell viability, apoptosis, endoplasmic reticulum (ER) stress, and inflammatory. In vivo, male C57BL/6 mice were fed a 60% high-fat diet (HFD) for 12 w. Then the lard in HFD was partially replaced with fish oil (FO) and olive oil (OO) at low or high proportions of energy (5% or 20%) to observe the ameliorative effects of the UFA supplement.ResultsAll UFAs significantly improved PA-induced cell viability impairment in INS-1E cells, and their alleviation on PA induced apoptosis, ER stress and inflammation were confirmed. Particularly, OA had better effects than EPA, DHA, and AA on attenuating cellular ER stress. In vivo, the diets with a low proportion of UFAs (5% of energy) had limited effects on HFD induced metabolic disorder, except for a slight improved intraperitoneal glucose tolerance in obese mice. However, when fed diets containing a high proportion of UFAs (20% of energy), both the FO and OO groups exhibited substantially improved glucose and lipid metabolism, such as decrease in total cholesterol (TC), low-density lipoprotein (LDL), fasting blood glucose (FBG), and fasting blood insulin (FBI)) and improvement of insulin sensitivity evidenced by intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT). Unexpectedly, FO resulted in abnormal elevation of the liver function index aspartate aminotransferase (AST) in serum. Pathologically, OO attenuated HFD-induced compensatory hyperplasia of pancreatic islets, while this effect was not obvious in the FO group.ConclusionsBoth MUFAs and PUFAs can effectively protect islet β cells from SFA-induced cellular lipotoxicity. In particular, both OA in vitro and OO in vivo showed superior activities on protecting islets function and enhance insulin sensitivity, suggesting that MUFAs might have greater potential for nutritional intervention on diabetes.

Dataset Information

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

Publications

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

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