scholarly journals Sterols, Oxysterols, and Accessible Cholesterol: Signalling for Homeostasis, in Immunity and During Development

2021 ◽  
Vol 12 ◽  
Author(s):  
William J. Griffiths ◽  
Yuqin Wang
Keyword(s):  
Plasma Membrane ◽  
Total Cell ◽  
Cholesterol Homeostasis ◽  
Microbial Pathogens ◽  
Membrane Cholesterol ◽  
Hedgehog Signalling ◽  
Signalling Molecule ◽  
Hedgehog Signalling Pathway ◽  
Patched 1 ◽  
Plasma Membrane Cholesterol

In this article we discuss the concept of accessible plasma membrane cholesterol and its involvement as a signalling molecule. Changes in plasma membrane accessible cholesterol, although only being minor in the context of total cholesterol plasma membrane cholesterol and total cell cholesterol, are a key regulator of overall cellular cholesterol homeostasis by the SREBP pathway. Accessible cholesterol also provides the second messenger between patched 1 and smoothened in the hedgehog signalling pathway important during development, and its depletion may provide a mechanism of resistance to microbial pathogens including SARS-CoV-2. We revise the hypothesis that oxysterols are a signalling form of cholesterol, in this instance as a rapidly acting and paracrine version of accessible cholesterol.

scholarly journals Reprogramming cholesterol metabolism in macrophages and its role in host defense against cholesterol-dependent cytolysins

2022 ◽  
Author(s):  
Min-Sub Lee ◽  
Steven J. Bensinger
Keyword(s):  
Plasma Membrane ◽  
Host Defense ◽  
Mammalian Cells ◽  
Cholesterol Metabolism ◽  
Current Knowledge ◽  
Membrane Integrity ◽  
Cholesterol Homeostasis ◽  
Metabolic Reprogramming ◽  
Membrane Cholesterol ◽  
Plasma Membrane Cholesterol

AbstractCholesterol is a critical lipid for all mammalian cells, ensuring proper membrane integrity, fluidity, and biochemical function. Accumulating evidence indicates that macrophages rapidly and profoundly reprogram their cholesterol metabolism in response to activation signals to support host defense processes. However, our understanding of the molecular details underlying how and why cholesterol homeostasis is specifically reshaped during immune responses remains less well understood. This review discusses our current knowledge of cellular cholesterol homeostatic machinery and introduces emerging concepts regarding how plasma membrane cholesterol is partitioned into distinct pools. We then discuss how proinflammatory signals can markedly reshape the cholesterol metabolism of macrophages, with a focus on the differences between MyD88-dependent pattern recognition receptors and the interferon signaling pathway. We also discuss recent work investigating the capacity of these proinflammatory signals to selectively reshape plasma membrane cholesterol homeostasis. We examine how these changes in plasma membrane cholesterol metabolism influence sensitivity to a set of microbial pore-forming toxins known as cholesterol-dependent cytolysins that specifically target cholesterol for their effector functions. We also discuss whether lipid metabolic reprogramming can be leveraged for therapy to mitigate tissue damage mediated by cholesterol-dependent cytolysins in necrotizing fasciitis and other related infections. We expect that advancing our understanding of the crosstalk between metabolism and innate immunity will help explain how inflammation underlies metabolic diseases and highlight pathways that could be targeted to normalize metabolic homeostasis in disease states.

scholarly journals Host but Not Parasite Cholesterol ControlsToxoplasmaCell Entry by Modulating Organelle Discharge

2003 ◽  
Vol 14 (9) ◽  
pp. 3804-3820 ◽  
Author(s):  
Isabelle Coppens ◽  
Keith A. Joiner
Keyword(s):  
Plasma Membrane ◽  
Host Cell ◽  
Parasitophorous Vacuole ◽  
Protozoan Parasite ◽  
Inhibitory Effect ◽  
Microbial Pathogens ◽  
Membrane Cholesterol ◽  
Cell Plasma ◽  
Host Plasma Membrane ◽  
Plasma Membrane Cholesterol

Host cell cholesterol is implicated in the entry and replication of an increasing number of intracellular microbial pathogens. Although uptake of viral particles via cholesterol-enriched caveolae is increasingly well described, the requirement of cholesterol for internalization of eukaryotic pathogens is poorly understood and is likely to be partly organism specific. We examined the role of cholesterol in active host cell invasion by the protozoan parasite Toxoplasma gondii. The parasitophorous vacuole membrane (PVM) surrounding T. gondii contains cholesterol at the time of invasion. Although cholesterol-enriched parasite apical organelles termed rhoptries discharge at the time of cell entry and contribute to PVM formation, surprisingly, rhoptry cholesterol is not necessary for this process. In contrast, host plasma membrane cholesterol is incorporated into the forming PVM during invasion, through a caveolae-independent mechanism. Unexpectedly, depleting host cell plasma membrane cholesterol blocks parasite internalization by reducing the release of rhoptry proteins that are necessary for invasion. Cholesterol back-addition into host plasma membrane reverses this inhibitory effect of depletion on parasite secretion. These data define a new mechanism by which host cholesterol specifically controls entry of an intracellular pathogen.

scholarly journals Monoclonal antibody detection of plasma membrane cholesterol microdomains responsive to cholesterol trafficking

2001 ◽  
Vol 42 (9) ◽  
pp. 1492-1500 ◽  
Author(s):  
Howard S. Kruth ◽  
Ina Ifrim ◽  
Janet Chang ◽  
Lia Addadi ◽  
Daniele Perl-Treves ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Plasma Membrane ◽  
Antibody Detection ◽  
Membrane Cholesterol ◽  
Cholesterol Trafficking ◽  
Plasma Membrane Cholesterol

scholarly journals Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Akash Das ◽  
Michael S Brown ◽  
Donald D Anderson ◽  
Joseph L Goldstein ◽  
Arun Radhakrishnan
Keyword(s):  
Plasma Membrane ◽  
Regulatory Mechanism ◽  
Low Density Lipoprotein ◽  
Human Fibroblasts ◽  
Density Lipoprotein ◽  
Cholesterol Homeostasis ◽  
Mutant Form ◽  
Perfringolysin O ◽  
Cholesterol Levels ◽  
Plasma Membrane Cholesterol

When human fibroblasts take up plasma low density lipoprotein (LDL), its cholesterol is liberated in lysosomes and eventually reaches the endoplasmic reticulum (ER) where it inhibits cholesterol synthesis by blocking activation of SREBPs. This feedback protects against cholesterol overaccumulation in the plasma membrane (PM). But how does ER know whether PM is saturated with cholesterol? In this study, we define three pools of PM cholesterol: (1) a pool accessible to bind 125I-PFO*, a mutant form of bacterial Perfringolysin O, which binds cholesterol in membranes; (2) a sphingomyelin(SM)-sequestered pool that binds 125I-PFO* only after SM is destroyed by sphingomyelinase; and (3) a residual pool that does not bind 125I-PFO* even after sphingomyelinase treatment. When LDL-derived cholesterol leaves lysosomes, it expands PM's PFO-accessible pool and, after a short lag, it also increases the ER's PFO-accessible regulatory pool. This regulatory mechanism allows cells to ensure optimal cholesterol levels in PM while avoiding cholesterol overaccumulation.

Cell culturing in a three-dimensional matrix affects the localization and properties of plasma membrane cholesterol

2009 ◽  
Vol 33 (10) ◽  
pp. 1079-1086 ◽  
Author(s):  
Nadezhda Stefanova ◽  
Galya Staneva ◽  
Diana Petkova ◽  
Teodora Lupanova ◽  
Roumen Pankov ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Three Dimensional ◽  
Membrane Cholesterol ◽  
Dimensional Matrix ◽  
Cell Culturing ◽  
Plasma Membrane Cholesterol
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