Effects of β-Cyclodextrin on the Structure of Sphingomyelin/Cholesterol Model Membranes

Jablin, Michael S.; Flasiński, Michał; Dubey, Manish; Ratnaweera, Dilru; Broniatowski, Marcin; Dynarowicz-Łątka, Patrycja; Majewski, Jarosław

doi:10.1016/j.bpj.2010.06.028

Cited by 22 publications

(19 citation statements)

References 42 publications

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“…21,22,24 To test cholesterol involvement, NPA fibroblasts were incubated with methyl-b-cyclodextrin, which sequesters this lipid without affecting SM. 31 Treatment for 24 h with 0.3 mM methyl-b-cyclodextrin had no effect on LC3-II levels ( Figure 5c) despite its efficiency in reducing cholesterol levels by 16% (Figure 5d), similar to the 15% SM reduction promoted by FB1.…”

Section: Resultsmentioning

confidence: 70%

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

et al. 2014

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Niemann Pick disease type A (NPA), which is caused by loss of function mutations in the acid sphingomyelinase (ASM) gene, is a lysosomal storage disorder leading to neurodegeneration. Yet, lysosomal dysfunction and its consequences in the disease are poorly characterized. Here we show that undegraded molecules build up in neurons of acid sphingomyelinase knockout mice and in fibroblasts from NPA patients in which autophagolysosomes accumulate. The latter is not due to alterations in autophagy initiation or autophagosome-lysosome fusion but because of inefficient autophago-lysosomal clearance. This, in turn, can be explained by lysosomal membrane permeabilization leading to cytosolic release of Cathepsin B. High sphingomyelin (SM) levels account for these effects as they can be induced in control cells on addition of the lipid and reverted on SM-lowering strategies in ASM-deficient cells. These results unveil a relevant role for SM in autophagy modulation and characterize autophagy anomalies in NPA, opening new perspectives for therapeutic interventions.

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Section: Resultsmentioning

confidence: 70%

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

et al. 2014

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“…4D). Treatment with 1 mmol/L methyl-b-cyclodextrin for 16 h, which removes cholesterol but not SM from the plasma membrane (23,24), had no effect on intracellular TG levels in Abcg1 SKD adipocytes ( Supplementary Fig. 1E), suggesting that free cholesterol in lipid rafts was not responsible for the reduced TG storage in those cells.…”

Section: Impaired Maturation In Stable Abcg1 Kd 3t3-l1 Adipocytesmentioning

confidence: 98%

Adipocyte ATP-Binding Cassette G1 Promotes Triglyceride Storage, Fat Mass Growth, and Human Obesity

et al. 2014

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The role of the ATP-binding cassette G1 (ABCG1) transporter in human pathophysiology is still largely unknown. Indeed, beyond its role in mediating free cholesterol efflux to HDL, the ABCG1 transporter equally promotes lipid accumulation in a triglyceride (TG)-rich environment through regulation of the bioavailability of lipoprotein lipase (LPL). Because both ABCG1 and LPL are expressed in adipose tissue, we hypothesized that ABCG1 is implicated in adipocyte TG storage and therefore could be a major actor in adipose tissue fat accumulation. Silencing of Abcg1 expression by RNA interference in 3T3-L1 preadipocytes compromised LPL-dependent TG accumulation during the initial phase of differentiation. Generation of stable Abcg1 knockdown 3T3-L1 adipocytes revealed that Abcg1 deficiency reduces TG storage and diminishes lipid droplet size through inhibition of Pparγ expression. Strikingly, local inhibition of adipocyte Abcg1 in adipose tissue from mice fed a high-fat diet led to a rapid decrease of adiposity and weight gain. Analysis of two frequent ABCG1 single nucleotide polymorphisms (rs1893590 [A/C] and rs1378577 [T/G]) in morbidly obese individuals indicated that elevated ABCG1 expression in adipose tissue was associated with increased PPARγ expression and adiposity concomitant to increased fat mass and BMI (haplotype AT>GC). The critical role of ABCG1 in obesity was further confirmed in independent populations of severe obese and diabetic obese individuals. This study identifies for the first time a major role of adipocyte ABCG1 in adiposity and fat mass growth and suggests that adipose ABCG1 might represent a potential therapeutic target in obesity.

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“…Thus, DRMs solubilization after cyclodextrin treatment was indicative of it being part of a raft component. In addition, if a biological process in living cells was disrupted by cyclodextrin treatment, the process was considered to be raft-based3456789. From the chemical point of view, cyclodextrins (CD) are composed of several glucose units, linked together by α -1,4-glucosidic bonds.…”

mentioning

confidence: 99%

Computational microscopy of cyclodextrin mediated cholesterol extraction from lipid model membranes

López

Vries

Marrink

2013

Sci Rep

109

118

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Beta-cyclodextrins (β-CDs) can form inclusion complexes with cholesterol, and are commonly used to manipulate cholesterol levels of biomembranes. In this work, we have used multiscale molecular dynamics simulations to provide a detailed view on the interaction between β-CDs and lipid model membranes. We show that cholesterol can be extracted efficiently upon adsorption of β-CD dimers at the membrane/water interface. However, extraction is only observed to occur spontaneously in membranes with high cholesterol levels. Free energy calculations reveal the presence of a kinetic barrier for cholesterol extraction in the case of low cholesterol content. Cholesterol uptake is facilitated in case of (poly)unsaturated lipid membranes, which increases the free energy of the membrane bound state of cholesterol. Comparing lipid/cholesterol compositions typical of liquid-disordered (Ld) and liquid-order (Lo) domains, we furthermore show that cholesterol is preferentially extracted from the disordered regions, in line with recent experimental data.

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Effects of β-Cyclodextrin on the Structure of Sphingomyelin/Cholesterol Model Membranes

Cited by 22 publications

References 42 publications

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

Adipocyte ATP-Binding Cassette G1 Promotes Triglyceride Storage, Fat Mass Growth, and Human Obesity

Computational microscopy of cyclodextrin mediated cholesterol extraction from lipid model membranes

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