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Cholesterol Delivery From the Plasma Membrane To the ER Is the Rate Limiting Factor of Acyl-Coenzyme A Acyltransferase Activity In Vivo
Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för cellbiologi. Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut. (Dr. Ingela Parmryd)
Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för cellbiologi. Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut. (Dr. Ingela Parmryd)
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Intracellular free cholesterol accumulation is toxic and has to be avoided. Acyl-CoA: cholesterol acyltransferase (ACAT) clears cells of cholesterol by forming cholesteryl esters (CE). Upon cold stress of Jurkat T cells at 0°C, plasma membrane cholesterol is reduced and both CEs and lipid droplets accumulate rapidly, resembling cells acutely loaded with exogenous cholesterol. ACAT is responsible for the increase, determined using the ACAT inhibitor Sandoz 58035. Cold stress accumulation of CEs requires the redistribution of plasma membrane cholesterol, shown by acute methyl-beta-cyclodextrin mediated cholesterol depletion. Filipin staining revealed that ACAT inhibition resulted in increased plasma membrane cholesterol levels. The plasma membrane of both cold stressed and cholesterol-loaded cells contained a lower proportion of ordered domains than control cells, assessed by laurdan staining. In vivo ACAT is limited by ER cholesterol availability that can be increased by redistribution of endogenous cholesterol.

Nyckelord [en]
ACAT, Cholesterol, Plasma membrane, Cholesteryl esters
Nationell ämneskategori
Cell- och molekylärbiologi
Forskningsämne
cellbiologi
Identifikatorer
URN: urn:nbn:se:su:diva-38350OAI: oai:DiVA.org:su-38350DiVA, id: diva2:309876
Tillgänglig från: 2010-04-09 Skapad: 2010-04-09 Senast uppdaterad: 2022-02-24Bibliografiskt granskad
Ingår i avhandling
1. Cholesterol in T cells: homeostasis, plasma membrane organization and signaling
Öppna denna publikation i ny flik eller fönster >>Cholesterol in T cells: homeostasis, plasma membrane organization and signaling
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The plasma membrane of eukaryotic cells contains cholesterol and glycosphingolipids enriched nanodomains known as lipid rafts; which are believed to exist in a liquid ordered (lo) state. Methyl-beta-cyclodextrin (MBCD) is used to deplete cellular cholesterol and a widespread assumption is that MBCD preferentially targets cholesterol in lipid rafts. To analyze this in T cells a progressive cholesterol extraction protocols was established. At 37ºC, MBCD treatment does not lead to the preferential loss of cholesterol from TX-DRMs. At 0ºC only 35% of total cholesterol could be extracted demonstrating that less than 35% of the cell’s cholesterol is found in the plasma membrane. Moreover, incubation of cells at 0ºC causes loss of plasma membrane cholesterol and an increase in cholesteryl esters. The increase in cholesterol esters upon cold exposure is linked to the cholesterol concentration induced activation of ACAT enzyme which converts cholesterol to cholesteryl esters. Cholesterol concentration specific activation of ACAT and conversion of cholesterol to cholesteryl esters during the loading of cholesterol onto T cells by MBCD was also observed. By using MBCD for progressive cholesterol depletion from T cells at 37ºC, the effect of cholesterol depletion on T cell signaling was addressed. At 10-20% cholesterol depletion levels, tyrosine phosphorylation is increased and ERK is activated. Peripheral actin polymerization, cell spreading and membrane protrusions are also triggered by limited cholesterol depletion. Upon limited cholesterol depletion aggregation of lipid rafts in the plasma membrane was observed. The aggregation of lipid rafts upon cholesterol depletion does not dependent on the signaling proteins such as Src-kinases. Upon cholesterol depletion there is an increase in overall plasma membrane order, indicative of more ordered domains forming at the expense of disordered domains.

Ort, förlag, år, upplaga, sidor
Stockholm: The Wenner-Gren Institute, Stockholm University, 2010. s. 76
Nyckelord
Plasma membrane, T cells, Cholesterol, Lipid rafts, Membrane organization, Cholesterol homeostasis, cholesteryl esters
Nationell ämneskategori
Cellbiologi
Forskningsämne
cellbiologi
Identifikatorer
urn:nbn:se:su:diva-38357 (URN)978-91-7447-055-0 (ISBN)
Disputation
2010-05-03, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Anmärkning
At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: In press. Tillgänglig från: 2010-04-11 Skapad: 2010-04-09 Senast uppdaterad: 2022-02-24Bibliografiskt granskad

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Mahammad, SaleemullaParmryd, Ingela

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Mahammad, SaleemullaParmryd, Ingela
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Avdelningen för cellbiologiWenner-Grens institut
Cell- och molekylärbiologi

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