Unraveling the Mystery Surrounding Cholesterol's Condensing Effect

Cao, Hui; Tokutake, Nobuya; Regen, Steven L.

doi:10.1021/ja039172x

Cited by 39 publications

(36 citation statements)

References 24 publications

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“…The finding that viruses not only utilize cellular lipids but also have mechanisms for perturbing lipid metabolism highlights a growing appreciation of the mechanisms by which viruses exploit cellular resources to favor their own propagation. Coupled with increasing evidence from model systems that minor changes in sterol structure are associated with significant changes in function including membrane dynamics, 20,21 lipid raft/domain formation, 22,23 and raft-associated receptor signaling, 24 our results provide strong motivation for on-going studies characterizing the functional role of 7-DHC in HBV biology. Finally, our results illustrate the power of untargeted analytical methods in identifying metabolites that are critical in disease states, including viral infection and pathogenesis.…”

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confidence: 60%

Identification of an Overabundant Cholesterol Precursor in Hepatitis B Virus Replicating Cells by Untargeted Lipid Metabolite Profiling

2009

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Viruses rely upon host lipid metabolic pathways for successful replication, and there is increasing interest in these pathways as novel therapeutic targets for antiviral drug discovery. Despite this, relatively little is known about the impact of viral infection on cellular lipid metabolism, and the specific lipid metabolites utilized by viruses have not yet been examined. We have applied liquid chromatography-mass spectroscopy (LC-MS) based discovery metabolite profiling (DMP) to identify lipid metabolites whose steady-state abundance is significantly altered by replication of hepatitis B virus (HBV), a major human pathogen. DMP indicated that although major lipid classes were unaffected by HBV, an ion of 367 m/z was overabundant in HBV+ cells by 18-fold. As shown by ion fragmentation mass spectrometry and co-injection with standard, the identity of this ion is 7-dehydrocholesterol (7-DHC), an immediate dehydrogenated precursor to cholesterol. While cholesterol has previously been demonstrated to be essential in the replication of many viruses, this is the first to show that viral replication is associated with the selective accumulation of 7-DHC. Most virological studies to date have relied upon methods that deplete all sterols and preclude the observation of any selectivity in sterol utilization by viral pathogens. Our study suggests that HBV may selectively utilize 7-DHC versus other sterols and prompts experiments investigating the functional significance of this enrichment and the elucidation of the mechanism by which it is achieved. The results also highlight the value of DMP as a method for identifying critical metabolites for viral infection.

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confidence: 60%

Identification of an Overabundant Cholesterol Precursor in Hepatitis B Virus Replicating Cells by Untargeted Lipid Metabolite Profiling

2009

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“…As discussed elsewhere, NNR experiments take molecular-level snapshots of bilayer organization by detecting and quantifying the thermodynamic tendency of exchangeable monomers to become nearest-neighbors of one another 5–7. Typically, two lipids of interest ( A and B ) are converted into exchangeable dimers ( AA , AB and BB ), which are then allowed to undergo monomer interchange via thiolate-disulfide interchange.…”

Section: Resultsmentioning

confidence: 99%

Reduced Sterol−Phospholipid Recognition in Curved Fluid Bilayers

2009

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Nearest-neighbor recognition experiments have been carried out in fluid liposomal membranes made from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol, using exchangeable dimers derived from 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine and cholesterol. In cholesterol-rich bilayers, the association between these two exchangeable lipids was reduced as the curvature of the membrane increases; that is, when the diameter of the liposomes was below ca. 200 nm. In sharp contrast, the mixing of these exchangeable lipids was close to random in the cholesterol-poor membranes, regardless of their curvature. The biological implications of these findings are briefly discussed.

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“…5,[33][34][35] In this cholesterol model, we have chosen the parameters and number of beads such that the relative lengths of the different hydrophilic and hydrophobic parts of the cholesterol molecule are consistent with our lipid model.…”

Section: Model and Simulation Methodsmentioning

confidence: 99%

Molecular Simulation of the DMPC-Cholesterol Phase Diagram

et al. 2010

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In this paper, we present a coarse-grained model of a hydrated saturated phospholipid bilayer (dimyristoylphosphatidylcholine, DMPC) containing cholesterol that we study using a hybrid dissipative particle dynamics-Monte Carlo method. This approach allows us to reach the time and length scales necessary to study structural and mechanical properties of the bilayer at various temperatures and cholesterol concentrations. The properties studied are the area per lipid, condensation, bilayer thickness, tail order parameters, bending modulus, and area compressibility. Our model quantitatively reproduces most of the experimental effects of cholesterol on these properties and reproduces the main features of the experimental phase and structure diagrams. We also present all-atom simulation results of the system and use these results to further validate the structure of our coarse-grained bilayer. On the basis of the changes in structural properties, we propose a temperature-composition structure diagram, which we compare with the experimental phase and structure diagrams. Attention is paid to the reliability and interpretation of the model and simulation method and of the different experimental techniques. The lateral organization of cholesterol in the bilayer is discussed.

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Unraveling the Mystery Surrounding Cholesterol's Condensing Effect

Cited by 39 publications

References 24 publications

Identification of an Overabundant Cholesterol Precursor in Hepatitis B Virus Replicating Cells by Untargeted Lipid Metabolite Profiling

Identification of an Overabundant Cholesterol Precursor in Hepatitis B Virus Replicating Cells by Untargeted Lipid Metabolite Profiling

Reduced Sterol−Phospholipid Recognition in Curved Fluid Bilayers

Molecular Simulation of the DMPC-Cholesterol Phase Diagram

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