Do Lipid Rafts Exist?

Leslie, Mitch

doi:10.1126/science.334.6059.1046-b

Cited by 61 publications

(38 citation statements)

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“…Although some controversy exists regarding the definition or even the existence of lipid rafts 46 , proteins involved in cell signaling clearly cluster in certain domains of the plasma membrane. Accumulation of free cholesterol of the plasma membrane is associated with increased signaling via TLR4 19, 20 , which reside in these domains – the presence of apoA-I or HDL reduces the cholesterol content of these rafts and TLR4 signaling in other cell types 20 .…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein AI and High-Density Lipoprotein Have Anti-Inflammatory Effects on Adipocytes via Cholesterol Transporters

Umemoto

Han

Mitra

et al. 2013

Circulation Research

105

112

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Rationale Macrophage accumulation in adipose tissue associates with insulin resistance and increased cardiovascular disease risk. We previously have shown that generation of reactive oxygen species (ROS) and monocyte chemotactic factors after exposure of adipocytes to saturated fatty acids (SFAs) such as palmitate occurs via translocation of NADPH oxidase 4 (NOX4) into lipid rafts (LRs). The anti-inflammatory effects of apolipoprotein A-I (apoA-I) and HDL on macrophages and endothelial cells appears to occur via cholesterol depletion of LRs. However, little is known concerning anti-inflammatory effects of HDL and apoA-I on adipocytes. Objective To determine whether apoA-I and HDL inhibit inflammation in adipocytes and adipose tissue, and whether this is dependent on LRs. Methods and Results In 3T3L-1 adipocytes, apoA-I, HDL and methyl-β-cyclodextrin inhibited chemotactic factor expression. ApoA-I and HDL also disrupted LRs, reduced plasma membrane cholesterol content, inhibited NOX4 translocation into LRs, and reduced palmitate-induced ROS generation and monocyte chemotactic factor expression. Silencing ABCA-1 abrogated the effect of apoA-I, but not HDL, while silencing ABCG-1 or SRB-1 abrogated the effect of HDL but not apoA-I. In vivo, apoA-I transgenic mice fed a high fat, high sucrose, cholesterol-containing diet showed reduced chemotactic factor and pro-inflammatory cytokine expression and reduced macrophage accumulation in adipose tissue. Conclusion ApoA-I and HDL have anti-inflammatory effects in adipocytes and adipose tissue similar to their effects in other cell types. These effects are consistent with disruption and removal of cholesterol from LRs, which are regulated by cholesterol transporters such as ABCA-1, ABCG-1 and SRB-1.

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein AI and High-Density Lipoprotein Have Anti-Inflammatory Effects on Adipocytes via Cholesterol Transporters

Umemoto

Han

Mitra

et al. 2013

Circulation Research

105

112

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“…Light DRMs, corresponding to classical LR, fractionate as low density, light fractions by discontinued sucrose density gradient centrifugation (SDGC) [15]. Notwithstanding controversies surrounding the existence of LR in an in vivo setting [16,17], including the question to what extent DRMs correspond to bona-fide native LR [18], recent experiments targeting critical signaling molecules to distinct membrane compartments [19][20][21][22], together with electron, fluorescent microscopy and nanoscopy (reviewed [23]) support the notion of a critical role of LR in the initiation of T cell signaling. Recently, a distinct type of microdomains, called high-density or heavy DRMs, was proposed to be involved in signaling in immune cells [21,22,24].…”

Section: Introductionmentioning

confidence: 99%

A specific type of membrane microdomains is involved in the maintenance and translocation of kinase active Lck to lipid rafts

et al. 2012

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“…Of note, a body of literature suggests that a substantial proportion of PrP C resides within cells in membrane (lipid) rafts [59,60], detergent-resistant membrane domains rich in cholesterol and sphingolipids, and it has been proposed that this localization of PrP C is critical for its ability to mediate oAβ toxicity [61]. Although the organizing principles that drive the composition of membrane rafts are still a matter of debate [62], it is likely that the molecular neighborhood of PrP C within these raft domains is not only governed by PrP C -lipid interactions but also by the relative affinity of PrP C towards other raft-resident proteins [63]. On the basis of these considerations it may not surprise that a majority of the aforementioned PrP C interactors (e.g., NCAM [31], the laminin recepetor precursor [64], integrins [65] and caveolin-1 [28]) have also been localized—at least transiently—in membrane rafts or in the aforementioned caveolae, a specialized subset of membrane rafts.…”

Section: Reviewmentioning

confidence: 99%

Overcoming barriers and thresholds – signaling of oligomeric Aβ through the prion protein to Fyn

Wang

Ren

Gunawardana

et al. 2013

Mol Neurodegeneration

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Evidence has been mounting for an involvement of the prion protein (PrP) in a molecular pathway assumed to play a critical role in the etiology of Alzheimer disease. A currently popular model sees oligomeric amyloid β (oAβ) peptides bind directly to PrP to emanate a signal that causes activation of the cytoplasmic tyrosine kinase Fyn, an essential player in a cascade of events that ultimately leads to NMDA receptor-mediated excitotoxicity and hyper-phosphorylation of tau. The model does not reveal, however, how extracellular binding of oAβ to PrP is communicated across the plasma membrane barrier to affect activation of Fyn. A scenario whereby PrP may adapt a transmembrane topology to affect Fyn activation in the absence of additional partners is currently not supported by evidence. A survey of known candidate PrP interactors leads to a small number of molecules that are known to acquire a transmembrane topology and understood to contribute to Fyn activation. Because multiple signaling pathways converge onto Fyn, a realistic model needs to take into account a reality of Fyn acting as a hub that integrates signals from multiple inhibitory and activating effectors. To clarify the role of PrP in oAβ-dependent excitotoxicity, future studies may need to incorporate experimental designs that can probe the contributions of Fyn modulator pathways and rely on analogous readouts, rather than threshold effects, known to underlie excitotoxic signaling.

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Do Lipid Rafts Exist?

Abstract: Many scientists argue that the molecular platforms that sail on the cell's outer membrane, known as lipid rafts, either don't exist or have no biological relevance, but their supporters insist the idea remains afloat.

Cited by 61 publications

References 0 publications

Apolipoprotein AI and High-Density Lipoprotein Have Anti-Inflammatory Effects on Adipocytes via Cholesterol Transporters

Apolipoprotein AI and High-Density Lipoprotein Have Anti-Inflammatory Effects on Adipocytes via Cholesterol Transporters

A specific type of membrane microdomains is involved in the maintenance and translocation of kinase active Lck to lipid rafts

Overcoming barriers and thresholds – signaling of oligomeric Aβ through the prion protein to Fyn

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