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European Journal of Cell Biology Dec 2023Lipid droplets (LD) are functionally conserved fat storage organelles found in all cell types. LDs have a unique structure comprising of a hydrophobic core of neutral... (Review)
Review
Lipid droplets (LD) are functionally conserved fat storage organelles found in all cell types. LDs have a unique structure comprising of a hydrophobic core of neutral lipids (fat), triacylglycerol (TAG) and cholesterol esters (CE) surrounded by a phospholipid monolayer. LD surface is decorated by a multitude of proteins and enzymes rendering this compartment functional. Accumulating evidence suggests that LDs originate from discrete ER-subdomains, demarcated by the lipodystrophy protein seipin, however, the mechanisms of which are not well understood. LD biogenesis factors together with biophysical properties of the ER membrane orchestrate spatiotemporal regulation of LD nucleation and growth at specific ER subdomains in response to metabolic cues. Defects in LD formation manifests in several human pathologies, including obesity, lipodystrophy, ectopic fat accumulation, and insulin resistance. Here, we review recent advances in understanding the molecular events during initial stages of eukaryotic LD assembly and discuss the critical role of factors that ensure fidelity of this process.
Topics: Humans; Lipid Droplets; Proteins; Endoplasmic Reticulum; Lipodystrophy
PubMed: 37742390
DOI: 10.1016/j.ejcb.2023.151362 -
Autophagy 2016Lipids stored in lipid droplets are hydrolyzed via either cytosolic lipases or a selective form of macroautophagy known as lipophagy. We recently demonstrated that...
Lipids stored in lipid droplets are hydrolyzed via either cytosolic lipases or a selective form of macroautophagy known as lipophagy. We recently demonstrated that chaperone-mediated autophagy (CMA) is required for the initiation of lipolysis by either of these independent lipolytic pathways. CMA selectively degrades the lipid droplet proteins perilipins (PLIN) 2 and 3 from the lipid droplet surface, thus, facilitating the recruitment of cytosolic lipases and autophagy effector proteins to the lipid droplets. PLIN2 phosphorylation was observed upon induction of lipolysis, but the phosphorylating kinase and the relation of this phosphorylation with CMA of PLIN2 remained unknown. Here, we report that phosphorylation of PLIN2 is dependent on AMPK and occurs after the interaction of PLIN2 with the CMA chaperone HSPA8/Hsc70. Our results highlight a role for posttranslational modifications in priming proteins to be amenable for degradation by CMA.
Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Lipid Droplets; Lipolysis; Mice; Models, Biological; Molecular Chaperones; NIH 3T3 Cells; Perilipin-2; Phosphorylation; Protein Kinase Inhibitors; Proteolysis
PubMed: 26902588
DOI: 10.1080/15548627.2015.1124226 -
Developmental Cell Jul 2017Lipid droplets (LDs) provide an "on-demand" source of fatty acids (FAs) that can be mobilized in response to fluctuations in nutrient abundance. Surprisingly, the amount...
Lipid droplets (LDs) provide an "on-demand" source of fatty acids (FAs) that can be mobilized in response to fluctuations in nutrient abundance. Surprisingly, the amount of LDs increases during prolonged periods of nutrient deprivation. Why cells store FAs in LDs during an energy crisis is unknown. Our data demonstrate that mTORC1-regulated autophagy is necessary and sufficient for starvation-induced LD biogenesis. The ER-resident diacylglycerol acyltransferase 1 (DGAT1) selectively channels autophagy-liberated FAs into new, clustered LDs that are in close proximity to mitochondria and are lipolytically degraded. However, LDs are not required for FA delivery to mitochondria but instead function to prevent acylcarnitine accumulation and lipotoxic dysregulation of mitochondria. Our data support a model in which LDs provide a lipid buffering system that sequesters FAs released during the autophagic degradation of membranous organelles, reducing lipotoxicity. These findings reveal an unrecognized aspect of the cellular adaptive response to starvation, mediated by LDs.
Topics: Amino Acids; Animals; Autophagy; Carnitine; Diacylglycerol O-Acyltransferase; Humans; Isotope Labeling; Lipid Droplets; Mechanistic Target of Rapamycin Complex 1; Mice; Mitochondria; Models, Biological; Multiprotein Complexes; Palmitic Acid; TOR Serine-Threonine Kinases; Triglycerides
PubMed: 28697336
DOI: 10.1016/j.devcel.2017.06.003 -
Cells Jul 2022Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease. The principal pathological feature of PD is the progressive...
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease. The principal pathological feature of PD is the progressive loss of dopaminergic neurons in the ventral midbrain. This pathology involves several cellular alterations: oxidative stress, mitochondrial dysfunction, loss of proteostasis, and autophagy impairment. Moreover, in recent years, lipid metabolism alterations have become relevant in PD pathogeny. The modification of lipid metabolism has become a possible way to treat the disease. Because of this, we analyzed the effect and possible mechanism of action of linoleic acid (LA) on an SH-SY5Y PD cell line model and a PD mouse model, both induced by 6-hydroxydopamine (6-OHDA) treatment. The results show that LA acts as a potent neuroprotective and anti-inflammatory agent in these PD models. We also observed that LA stimulates the biogenesis of lipid droplets and improves the autophagy/lipophagy flux, which resulted in an antioxidant effect in the in vitro PD model. In summary, we confirmed the neuroprotective effect of LA in vitro and in vivo against PD. We also obtained some clues about the novel neuroprotective mechanism of LA against PD through the regulation of lipid droplet dynamics.
Topics: Animals; Autophagy; Cell Line, Tumor; Humans; Linoleic Acid; Lipid Droplets; Mice; Neuroblastoma; Neurodegenerative Diseases; Oxidopamine; Parkinson Disease
PubMed: 35892594
DOI: 10.3390/cells11152297 -
Cell Host & Microbe Jun 2023The ability of Mycobacterium tuberculosis (Mtb) to establish latency affects disease and response to treatment. The host factors that influence the establishment of...
The ability of Mycobacterium tuberculosis (Mtb) to establish latency affects disease and response to treatment. The host factors that influence the establishment of latency remain elusive. We engineered a multi-fluorescent Mtb strain that reports survival, active replication, and stressed non-replication states and determined the host transcriptome of the infected macrophages in these states. Additionally, we conducted a genome-wide CRISPR screen to identify host factors that modulated the phenotypic state of Mtb. We validated hits in a phenotype-specific manner and prioritized membrane magnesium transporter 1 (MMGT1) for a detailed mechanistic investigation. Mtb infection of MMGT1-deficient macrophages promoted a switch to persistence, upregulated lipid metabolism genes, and accumulated lipid droplets during infection. Targeting triacylglycerol synthesis reduced both droplet formation and Mtb persistence. The orphan G protein-coupled receptor GPR156 is a key inducer of droplet accumulation in ΔMMGT1 cells. Our work uncovers the role of MMGT1-GPR156-lipid droplets in the induction of Mtb persistence.
Topics: Mycobacterium tuberculosis; Lipid Droplets; Macrophages; Lipid Metabolism
PubMed: 37269834
DOI: 10.1016/j.chom.2023.05.009 -
Nature Communications Jan 2024Lipid droplets (LDs) are dynamic lipid storage organelles that can be degraded by autophagy machinery to release neutral lipids, a process called lipophagy. However,...
Lipid droplets (LDs) are dynamic lipid storage organelles that can be degraded by autophagy machinery to release neutral lipids, a process called lipophagy. However, specific receptors and regulation mechanisms for lipophagy remain largely unknown. Here, we identify that ATG14, the core unit of the PI3KC3-C1 complex, also targets LD and acts as an autophagic receptor that facilitates LD degradation. A negative regulator, Syntaxin18 (STX18) binds ATG14, disrupting the ATG14-ATG8 family members interactions and subverting the PI3KC3-C1 complex formation. Knockdown of STX18 activates lipophagy dependent on ATG14 not only as the core unit of PI3KC3-C1 complex but also as the autophagic receptor, resulting in the degradation of LD-associated anti-viral protein Viperin. Furthermore, coronavirus M protein binds STX18 and subverts the STX18-ATG14 interaction to induce lipophagy and degrade Viperin, facilitating virus production. Altogether, our data provide a previously undescribed mechanism for additional roles of ATG14 in lipid metabolism and virus production.
Topics: Lipid Droplets; Lipid Metabolism; Proteins; Autophagy
PubMed: 38245527
DOI: 10.1038/s41467-024-44978-w -
Journal of Cell Science Mar 2022Lipid droplets (LDs) are ubiquitous organelles that store and supply lipids for energy metabolism, membrane synthesis and production of lipid-derived signaling...
Lipid droplets (LDs) are ubiquitous organelles that store and supply lipids for energy metabolism, membrane synthesis and production of lipid-derived signaling molecules. While compositional differences in the phospholipid monolayer or neutral lipid core of LDs impact their metabolism and function, the proteome of LDs has emerged as a major influencer in all aspects of LD biology. The perilipins (PLINs) are the most studied and abundant proteins residing on the LD surface. This Cell Science at a Glance and the accompanying poster summarize our current knowledge of the common and unique features of the mammalian PLIN family of proteins, the mechanisms through which they affect cell metabolism and signaling, and their links to disease.
Topics: Animals; Lipid Droplets; Lipid Metabolism; Mammals; Perilipins; Phospholipids; Protein Binding; Proteome
PubMed: 35260890
DOI: 10.1242/jcs.259501 -
Autophagy Oct 2023Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly, and there is currently no clinical treatment targeting the...
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly, and there is currently no clinical treatment targeting the primary impairment of AMD. The earliest clinical hallmark of AMD is drusen, which are yellowish spots mainly composed of lipid droplets (LDs) accumulated under the retinal pigment epithelium (RPE). However, the potential pathogenic role of this excessive LD accumulation in AMD is yet to be determined, partially due to a lack of chemical tools to manipulate LDs specifically. Here, we employed our recently developed Lipid Droplets·AuTophagy Tethering Compounds (LD∙ATTECs) to degrade LDs and to evaluate its consequence on the AMD-like phenotypes in apoe (apolipoprotein E; B6/JGpt-Apoe/Gpt) mouse model. apoe mice fed with high-fat diet (apoe-HFD) exhibited excessive LD accumulation in the retina, particularly with AMD-like phenotypes including RPE degeneration, Bruch's membrane (BrM) thickening, drusen-like deposits, and photoreceptor dysfunction. LD·ATTEC treatment significantly cleared LDs in RPE/choroidal tissues without perturbing lipid synthesis-related proteins and rescued RPE degeneration and photoreceptor dysfunction in apoe-HFD mice. This observation implied a causal relationship between LD accumulation and AMD-relevant phenotypes. Mechanically, the apoe-HFD mice exhibited elevated oxidative stress and inflammatory signals, both of which were mitigated by the LD·ATTEC treatment. Collectively, this study demonstrated that LD accumulation was a trigger for the process of AMD and provided entry points for the treatment of the initial insult of AMD by degrading LDs. AMD: age-related macular degeneration; : apolipoprotein E; ATTECs: autophagy-tethering compounds; BODIPY: boron-dipyrromethene; BrM: Bruch's membrane; ERG: electroretinogram; HFD: high-fat diet; LD·ATTECs: Lipid Droplets·AuTophagy Tethering Compounds; LDs: lipid droplets; OA: oleic acid; OPL: outer plexiform layer; ROS: reactive oxygen species; RPE: retinal pigment epithelium.
Topics: Mice; Animals; Lipid Droplets; Autophagy; Macular Degeneration; Retinal Pigment Epithelium; Apolipoproteins E; Phenotype; Apolipoproteins
PubMed: 37266932
DOI: 10.1080/15548627.2023.2220540 -
Cells Aug 2019Lipid droplets (LDs) are a crucial part of lipid storage; thus, they are important players in a variety of diseases that are affected by lipid imbalances such as...
Lipid droplets (LDs) are a crucial part of lipid storage; thus, they are important players in a variety of diseases that are affected by lipid imbalances such as obesity, fatty liver disease, type 2 diabetes, Alzheimer's disease, cardiovascular disease, and cancer [...].
Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fatty Liver; Humans; Lipid Droplets; Lipid Metabolism; Mitochondria; Neoplasms; Obesity
PubMed: 31454885
DOI: 10.3390/cells8090974 -
Current Opinion in Structural Biology Jun 2023Cells store lipids as a reservoir of metabolic energy and membrane component precursors in organelles called lipid droplets (LDs). LD formation occurs in the endoplasmic... (Review)
Review
Cells store lipids as a reservoir of metabolic energy and membrane component precursors in organelles called lipid droplets (LDs). LD formation occurs in the endoplasmic reticulum (ER) at LD assembly complexes (LDAC), consisting of an oligomeric core of seipin and accessory proteins. LDACs determine the sites of LD formation and are required for this process to occur normally. Seipin oligomers form a cage-like structure in the membrane that may serve to facilitate the phase transition of neutral lipids in the membrane to form an oil droplet within the LDAC. Modeling suggests that, as the LD grows, seipin anchors it to the ER bilayer and conformational shifts of seipin transmembrane segments open the LDAC dome toward the cytoplasm, enabling the emerging LD to egress from the ER.
Topics: Lipid Droplets; Proteins; Endoplasmic Reticulum; Lipids; Lipid Metabolism
PubMed: 37150040
DOI: 10.1016/j.sbi.2023.102606