SNARE proteins mediate fusion between cytosolic lipid droplets and are implicated in insulin sensitivity

Boström, Pontus; Andersson, Linda; Rutberg, Mikael; Perman, Jeanna; Lidberg, Ulf; Johansson, Bengt R.; Fernández-Rodrı́guez, Julia; Ericson, Johanna; Nilsson, Tommy; Borén, Jan; Olofsson, Sven-Olof

doi:10.1038/ncb1648

Cited by 315 publications

(312 citation statements)

References 27 publications

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“…Mutual fusion catalyzed by the SNARE proteins, SNAP23, syntaxin-5, and VAMP4, is a possible mechanism of LD growth (Bostrom et al 2007), however, it may not be an exclusive LD growth mechanism in mammalian cells as only a low frequency of fusion was observed by live imaging (Wolins et al 2005;Thiele et al 2008). Repetitive fusion also does not readily explain the uniform incorporation of newly formed TG to existing LDs (Cheng et al 2009).…”

Section: Structure and Function Of Lipid Dropletmentioning

confidence: 99%

Not Just Fat: The Structure and Function of the Lipid Droplet

Fujimoto

Parton²

2011

Cold Spring Harbor Perspectives in Biology

408

336

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Lipid droplets (LDs) are independent organelles that are composed of a lipid ester core and a surface phospholipid monolayer. Recent studies have revealed many new proteins, functions, and phenomena associated with LDs. In addition, a number of diseases related to LDs are beginning to be understood at the molecular level. It is now clear that LDs are not an inert store of excess lipids but are dynamically engaged in various cellular functions, some of which are not directly related to lipid metabolism. Compared to conventional membrane organelles, there are still many uncertainties concerning the molecular architecture of LDs and how each function is placed in a structural context. Recent findings and remaining questions are discussed.

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Section: Structure and Function Of Lipid Dropletmentioning

confidence: 99%

Not Just Fat: The Structure and Function of the Lipid Droplet

Fujimoto

Parton²

2011

Cold Spring Harbor Perspectives in Biology

408

336

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“…Possible candidates to mediate LD targeting are the soluble NSF attachment protein receptors (SNAREs). Long implicated in LD fusion, 12 SNAREs have recently been described to mediate autophagosome biogenesis. 13,14 Another possibility is LC3, which is a protein critical for autophagosome membrane formation.…”

Section: Intracellular Lipids Are Degraded By Lipophagymentioning

confidence: 99%

Regulation of lipid stores and metabolism by lipophagy

2012

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Intracellular lipids are stored in lipid droplets (LDs) and metabolized by cytoplasmic neutral hydrolases to supply lipids for cell use. Recently, an alternative pathway of lipid metabolism through the lysosomal degradative pathway of autophagy has been described and termed lipophagy. In this form of lipid metabolism, LD triglycerides (TGs) and cholesterol are taken up by autophagosomes and delivered to lysosomes for degradation by acidic hydrolases. Free fatty acids generated by lipophagy from the breakdown of TGs fuel cellular rates of mitochondrial b-oxidation. Lipophagy therefore functions to regulate intracellular lipid stores, cellular levels of free lipids such as fatty acids and energy homeostasis. The amount of lipid metabolized by lipophagy varies in response to the extracellular supply of nutrients. The ability of the cell to alter the amount of lipid targeted for autophagic degradation depending on nutritional status demonstrates that this process is selective. Intracellular lipids themselves regulate levels of autophagy by unclear mechanisms. Impaired lipophagy can lead to excessive tissue lipid accumulation such as hepatic steatosis, alter hypothalamic neuropeptide release to affect body mass, block cellular transdifferentiation and sensitize cells to death stimuli. Future studies will likely identify additional mechanisms by which lipophagy regulates cellular physiology, making this pathway a potential therapeutic target in a variety of diseases. Open QuestionsHow does the autophagic machinery selectively target stored lipids for degradation in response to changes in nutrient levels? What are the relative contributions of cytosolic lipolysis and lipophagy to lipid metabolism in different cell types, and is there cross-talk between the two pathways? What are the mechanisms by which intracellular lipids and other factors regulate levels of lipophagy? Do defects in lipophagy underlie human disease and can lipophagy be a therapeutic target? Intracellular lipids are essential to cells as an energy source, structural components for membranes, synthetic building blocks for other molecules, such as hormones, and as mediators of cell signaling. The ability to safely store adequate, but not excessive, amounts of lipids and to metabolize them when needed is critical for cell function and survival. The recent finding that lipids can be selectively degraded by the lysosomal pathway of macroautophagy through a process termed lipophagy 1 has opened up a new understanding of how lipid metabolism regulates cellular physiology and pathophysiology. Many new functions for autophagic lipid metabolism have now been defined in diverse cellular processes ranging from transdifferentiation to resistance to death. Intracellular Lipids are Degraded by LipophagyTGs and cholesterol are safely stored as neutral lipids in specialized cellular organelles called LDs. 2,3 Until recently, the breakdown of LD-stored TG and cholesterol was attributed exclusively to the actions of cytosolic hydrolytic enzymes or lipases. The role of l...

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“…In addition to regulating lipolysis, we have also identified a further, distinct function for γ-synuclein in adipocytes: regulating the formation of SNARE complexes that are involved in lipid droplet fusion, contributing to lipid accumulation in the adipocyte and a consequent increase in its size (13)(14)(15). This provides an intriguing echo of the function of α-synuclein in neuronal synapses, where it enhances neurotransmitter exocytosis by promoting the assembly of SNARE complexes, with a pivotal role in synaptic vesicle docking and fusion pore formation at the plasma membrane (11).…”

Section: Discussionmentioning

confidence: 99%

“…In neuronal synapses, α-synuclein is involved in regulation of synaptic vesicle fusion with the cell membrane by promoting the assembly of SNARE complexes (11). In adipocytes, SNARE complexes have been implicated in lipid droplet formation and growth by fusion between neutral TAG packaged within amphipathic lipoproteins and the lipid droplet phospholipid monolayer (12)(13)(14)(15). To determine whether γ-synuclein may regulate the efficiency of this fusion mechanism, we quantified the assembled SNARE complexes in epididymal WAT lysates by measuring the amount of VAMP-4 (vSNARE) that coimmunoprecipitated with syntaxin-5 (tSNARE).…”

Section: γ-Synuclein Promotes Assembly Of Snare Complexes In Wat Andmentioning

confidence: 99%

Increased lipolysis and altered lipid homeostasis protect γ-synuclein–null mutant mice from diet-induced obesity

Millership

Ninkina

Guschina

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Synucleins are a family of homologous proteins principally known for their involvement in neurodegeneration. γ-Synuclein is highly expressed in human white adipose tissue and increased in obesity.Here we show that γ-synuclein is nutritionally regulated in white adipose tissue whereas its loss partially protects mice from high-fat diet (HFD)-induced obesity and ameliorates some of the associated metabolic complications. Compared with HFD-fed WT mice, HFD-fed γ-synuclein-null mutant mice display increased lipolysis, lipid oxidation, and energy expenditure, and reduced adipocyte hypertrophy. Knockdown of γ-synuclein in adipocytes causes redistribution of the key lipolytic enzyme ATGL to lipid droplets and increases lipolysis. γ-Synuclein-deficient adipocytes also contain fewer SNARE complexes of a type involved in lipid droplet fusion. We hypothesize that γ-synuclein may deliver SNAP-23 to the SNARE complexes under lipogenic conditions. Via these independent but complementary roles, γ-synuclein may coordinately modulate lipid storage by influencing lipolysis and lipid droplet formation. Our data reveal γ-synuclein as a regulator of lipid handling in adipocytes, the function of which is particularly important in conditions of nutrient excess.U nderstanding the link between increased adiposity and the development of metabolic disease may reveal novel therapeutic targets to counter the rising pandemic of obesity. Inhibiting adipose tissue expansion alone is likely to worsen metabolic outcome, as evidenced by human syndromes of lipodystrophy, whereby inappropriately decreased adipose mass causes severe metabolic disorders (1). Indeed, adipose tissue dysfunction and/ or exceeded adipose storage capacity may underlie ectopic lipid accumulation and lipotoxicity in obesity (2). Therefore, a major challenge is to identify pathways via which adiposity can be reduced without concomitant increases in circulating lipids and attendant metabolic disease. Achieving this goal requires a better understanding of the molecular mechanisms that regulate lipid metabolism and storage in adipocytes, particularly in times of energy surplus.γ-Synuclein belongs to the synuclein family of proteins, whose founder member α-synuclein is best known for its links with neurodegenerative diseases, most notably Parkinson disease (3). To date, no clear cellular role is attributed to γ-synuclein, and ablation of γ-synuclein causes only minor changes in the nervous system (4-7). Recently, we and others have reported high levels of γ-synuclein expression in adipose tissue of humans and other mammals (8,9). Moreover, expression of γ-synuclein is increased in the adipose tissue of obese humans and decreased during caloric restriction (8).Here we demonstrate that γ-synuclein-null mice display significantly reduced adiposity and fewer metabolic derangements compared with WT mice following high-fat feeding. This appears to result from increased adipocyte lipolysis coupled to enhanced whole-body lipid oxidation and energy expenditure. At a molecular level, we i...

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SNARE proteins mediate fusion between cytosolic lipid droplets and are implicated in insulin sensitivity

Cited by 315 publications

References 27 publications

Not Just Fat: The Structure and Function of the Lipid Droplet

Not Just Fat: The Structure and Function of the Lipid Droplet

Regulation of lipid stores and metabolism by lipophagy

Increased lipolysis and altered lipid homeostasis protect γ-synuclein–null mutant mice from diet-induced obesity

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