Cytosolic Lipid Droplets Increase in Size by Microtubule-Dependent Complex Formation

Boström, Pontus; Rutberg, Mikael; Ericsson, Johanna; Holmdahl, Peter; Andersson, Linda; Frohman, Michael A.; Borén, Jan; Olofsson, Sven-Olof

doi:10.1161/01.atv.0000179676.41064.d4

Cited by 155 publications

(169 citation statements)

References 23 publications

(24 reference statements)

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“…LDs show both random short-distance and microtubule-based directional long-distance movements (Welte 2009). Dynein (Gross et al 2000;Bostrom et al 2005) and kinesin-1 (Shubeita et al 2008) (minusend and plus-end motors, respectively) were found to associate with LDs. In Drosophila melanogaster, a PAT protein homolog, LSD2, regulates bidirectional LD movement by coordinating opposite-polarity motor proteins (Welte et al 2005).…”

Section: Lipid Droplet Motilitymentioning

confidence: 99%

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

Fujimoto

Parton²

2011

Cold Spring Harbor Perspectives in Biology

392

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: Lipid Droplet Motilitymentioning

confidence: 99%

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

Fujimoto

Parton²

2011

Cold Spring Harbor Perspectives in Biology

392

336

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“…Oxidative injury to the phospholipid monolayer around the droplets, altered expression of PAT in NASH and the interaction of droplets with cytoskeletal elements suggests that dysfunction of these organelles may be central to NASH pathogenesis [41][42][43][44][45][46]. Potentially important factors include altered droplet fusion and interaction with the cytoskeleton [47,48]. Using conventional fixation techniques and protocol morphometry, we recently demonstrated an association between the accumulation of small-to-medium sized lipid droplets, cellular keratin depletion, MDBs and cellular ballooning, suggesting impaired fat droplet metabolism in NASH [31].…”

Section: Fat Dropletsmentioning

confidence: 99%

Ultrastructural findings in human nonalcoholic steatohepatitis

Jayakumar

Guillot

Argo

et al. 2011

Expert Review of Gastroenterology & Hepatology

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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%

“…Mature WAT adipocyte lipolysis was quantified by glycerol release under basal [i.e., 200 nM (R)-(-)-N 6 -(2-phenylisopropyl)adenosine] and catecholamine-stimulated [i.e., 200 nM (R)-(-)-N 6 -(2-phenylisopropyl)adenosine plus 10 μM isoproterenol] conditions. In 3T3-L1 adipocytes and MEFs, lipolysis was determined by 14 C release from cells loaded overnight with [ 14 C]oleate, serum-deprived for 2 h, then stimulated for 30 min with or without 1 nM or 1 μM isoproterenol as indicated, essentially as described previously (26).…”

Section: Methodsmentioning

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%

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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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Cytosolic Lipid Droplets Increase in Size by Microtubule-Dependent Complex Formation

Cited by 155 publications

References 23 publications

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

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

Ultrastructural findings in human nonalcoholic steatohepatitis

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

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