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.

Direct Electrochemical Evaluation of Plasma Membrane Cholesterol in Live Mammalian Cells

2007 ◽  
Vol 129 (37) ◽  
pp. 11352-11353 ◽  
Author(s):  
Dechen Jiang ◽  
Anando Devadoss ◽  
M. Simona Palencsár ◽  
Danjun Fang ◽  
Nicole M. White ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Mammalian Cells ◽  
Membrane Cholesterol ◽  
Electrochemical Evaluation ◽  
Plasma Membrane Cholesterol

scholarly journals Sphingomyelinase activates GLUT4 translocation via a cholesterol-dependent mechanism

2004 ◽  
Vol 286 (2) ◽  
pp. C317-C329 ◽  
Author(s):  
Ping Liu ◽  
Brian J. Leffler ◽  
Lara K. Weeks ◽  
Guoli Chen ◽  
Christine M. Bouchard ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Glucose Transporter ◽  
Degradation Products ◽  
Membrane Integrity ◽  
Time Dependent ◽  
Membrane Cholesterol ◽  
Glut4 Translocation ◽  
Dose Dependent ◽  
Plasma Membrane Cholesterol ◽  
Dependent Mechanism

A basis for the insulin mimetic effect of sphingomyelinase on glucose transporter isoform GLUT4 translocation remains unclear. Because sphingomyelin serves as a major determinant of plasma membrane cholesterol and a relationship between plasma membrane cholesterol and GLUT4 levels has recently become apparent, we assessed whether GLUT4 translocation induced by sphingomyelinase resulted from changes in membrane cholesterol content. Exposure of 3T3-L1 adipocytes to sphingomyelinase resulted in a time-dependent loss of sphingomyelin from the plasma membrane and a concomitant time-dependent accumulation of plasma membrane GLUT4. Degradation products of sphingomyelin did not mimic this stimulatory action. Plasma membrane cholesterol amount was diminished in cells exposed to sphingomyelinase. Restoration of membrane cholesterol blocked the stimulatory effect of sphingomyelinase. Increasing concentrations of methyl-β-cyclodextrin, which resulted in a dose-dependent reversible decrease in membrane cholesterol, led to a dose-dependent reversible increase in GLUT4 incorporation into the plasma membrane. Although increased plasma membrane GLUT4 content by cholesterol extraction with concentrations of methyl-β-cyclodextrin above 5 mM most likely reflected decreased GLUT4 endocytosis, translocation stimulated by sphingomyelinase or concentrations of methyl-β-cyclodextrin below 2.5 mM occurred without any visible changes in the endocytic retrieval of GLUT4. Furthermore, moderate loss of cholesterol induced by sphingomyelinase or low concentrations of methyl-β-cyclodextrin did not alter membrane integrity or increase the abundance of other plasma membrane proteins such as the GLUT1 glucose transporter or the transferrin receptor. Regulation of GLUT4 translocation by moderate cholesterol loss did not involve known insulin-signaling proteins. These data reveal that sphingomyelinase enhances GLUT4 exocytosis via a novel cholesterol-dependent mechanism.

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 Plasma Membrane Cholesterol Modulates Cellular Vacuolation Induced by the Helicobacter pylori Vacuolating Cytotoxin

2002 ◽  
Vol 70 (8) ◽  
pp. 4112-4123 ◽  
Author(s):  
Hetal K. Patel ◽  
David C. Willhite ◽  
Rakhi M. Patel ◽  
Dan Ye ◽  
Christopher L. Williams ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Plasma Membrane ◽  
Mammalian Cells ◽  
De Novo ◽  
Detectable Effect ◽  
Membrane Cholesterol ◽  
Vacuolating Cytotoxin ◽  
Vacuole Biogenesis ◽  
Plasma Membrane Cholesterol

ABSTRACT The Helicobacter pylori vacuolating cytotoxin (VacA) induces the degenerative vacuolation of mammalian cells both in vitro and in vivo. Here, we demonstrate that plasma membrane cholesterol is essential for vacuolation of mammalian cells by VacA. Vacuole biogenesis in multiple cell lines was completely blocked when cholesterol was extracted selectively from the plasma membrane by using β-cyclodextrins. Moreover, increasing plasma membrane cholesterol levels strongly potentiated VacA-induced vacuolation. In contrast, inhibiting de novo biosynthesis of cholesterol with lovastatin or compactin had no detectable effect on vacuolation. While depletion of plasma membrane cholesterol has been shown to interfere with both clathrin-mediated endocytosis and caveola-dependent endocytosis, neither of these two internalization pathways was found to be essential for vacuolation of cells by VacA. Depleting plasma membrane cholesterol attenuated the entry of VacA into HeLa cells. In addition, β-cyclodextrin reagents blocked vacuolation of cells that were either preloaded with VacA or had VacA directly expressed within the cytosol. Collectively, our results suggest that plasma membrane cholesterol is important for both the intoxication mechanism of VacA and subsequent vacuole biogenesis.

Plasma Membrane Cholesterol:  A Possible Barrier to Intracellular Oxygen in Normal and Mutant CHO Cells Defective in Cholesterol Metabolism†

Biochemistry ◽  
2003 ◽  
Vol 42 (1) ◽  
pp. 23-29 ◽  
Author(s):  
Nadeem Khan ◽  
Jiangang Shen ◽  
Ta Yuan Chang ◽  
Catherine C. Chang ◽  
Peter C. W. Fung ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cho Cells ◽  
Cholesterol Metabolism ◽  
Membrane Cholesterol ◽  
Plasma Membrane Cholesterol

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
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