Sphingomyelin in High-Density Lipoproteins: Structural Role and Biological Function

Martínez‐Beamonte, Roberto; Lou-Bonafonte, José Manuel; Martínez-Gracia, María Victoria; Osada, Jesús

doi:10.3390/ijms14047716

Cited by 67 publications

(53 citation statements)

References 180 publications

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“…The fluidity of the HDL, as well as its CEC, is considered to be inversely related to the sphingomyelin content of the HDL. The sphingomyelin content of the HDL subpopulations remains, at present, controversial . The complexity of sphingomyelin species, their distribution in the different HDL particles, and their role in HDL fluidity and CEC is considered a promising target for future studies …”

Section: Discussionmentioning

confidence: 99%

“…[47] The complexity of sphingomyelin species, their distribution in the different HDL particles, and their role in HDL fluidity and CEC is considered a promising target for future studies. [47] Our study has limitations. First, cholesterol efflux was measured ex vivo, but the transport of the cholesterol to the liver, the second part of the reverse cholesterol transport was not assessed.…”

Section: Discussionmentioning

confidence: 99%

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Determinants of HDL Cholesterol Efflux Capacity after Virgin Olive Oil Ingestion: Interrelationships with Fluidity of HDL Monolayer

Fernández‐Castillejo¹,

Rubió²,

Hernáez

et al. 2017

Molecular Nutrition Food Res

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Scope Cholesterol efflux capacity of HDL (CEC) is inversely associated with cardiovascular risk. HDL composition, fluidity, oxidation, and size are related with CEC. We aimed to assess which HDL parameters were CEC determinants after virgin olive oil (VOO) ingestion. Methods and Results Post-hoc analyses from the VOHF study, a crossover intervention with three types of VOO. We assessed the relationship of 3-week changes in HDL-related variables after intervention periods with independence of the type of VOO. After univariate analyses, mixed linear models were fitted with variables related with CEC and fluidity. Fluidity and Apolipoprotein (Apo)A-I content in HDL was directly associated, and HDL oxidative status inversely, with CEC. A reduction in free cholesterol, an increase in triglycerides in HDL, and a decrease in small HDL particle number or an increase in HDL mean size, were associated to HDL fluidity. Conclusions HDL fluidity, ApoA-I concentration, and oxidative status are major determinants for CEC after VOO. The impact on CEC of changes in free cholesterol and triglycerides in HDL, and those of small HDL or HDL mean size, could be mechanistically linked through HDL fluidity. Our work points out novel therapeutic targets to improve HDL functionality in humans through nutritional or pharmacological interventions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Determinants of HDL Cholesterol Efflux Capacity after Virgin Olive Oil Ingestion: Interrelationships with Fluidity of HDL Monolayer

Fernández‐Castillejo¹,

Rubió²,

Hernáez

et al. 2017

Molecular Nutrition Food Res

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“…Sphingomyelin is a constituent of all lipoproteins and affects HDL-mediated cholesterol efflux, hepatic cholesterol uptake, clearance of triglyceride rich remnants, aggregation and binding of LDL to the aterial wall [44–46]. Further research is needed to clarify whether reduced hepatic cholesterol is a consequence of low sphingomyelin in these animals.…”

Section: Discussionmentioning

confidence: 99%

Lipid abnormalities in alpha/beta2-syntrophin null mice are independent from ABCA1

Hebel

Eisinger

Neumeier

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The syntrophins alpha (SNTA) and beta 2 (SNTB2) are molecular adaptor proteins shown to stabilize ABCA1, an essential regulator of HDL cholesterol. Furthermore, SNTB2 is involved in glucose stimulated insulin release. Hyperglycemia and dyslipidemia are characteristic features of the metabolic syndrome, a serious public health problem with rising prevalence. Therefore, it is important to understand the role of the syntrophins herein. Mice deficient for both syntrophins (SNTA/B2−/−) have normal insulin and glucose tolerance, hepatic ABCA1 protein and cholesterol. When challenged with a HFD, wild type and SNTA/B2−/− mice have similar weight gain, adiposity, serum and liver triglycerides. Hepatic ABCA1, serum insulin and insulin sensitivity are normal while glucose tolerance is impaired. Liver cholesterol is reduced, and expression of SREBP2 and HMG-CoA-R is increased in the knockout mice. Scavenger receptor-BI (SR-BI) protein is strongly diminished in the liver of SNTA/B2−/− mice while SR-BI binding protein NHERF1 is not changed and PDZK1 is even induced. Knock-down of SNTA, SNTB2 or both has no effect on hepatocyte SR-BI and PDZK1 proteins. Further, SR-BI levels are not reduced in brown adipose tissue of SNTA/B2−/− mice excluding that syntrophins directly stabilize SR-BI. SR-BI stability is regulated by MAPK and phosphorylated ERK2 is induced in the liver of the knock-out mice. Blockage of ERK activity upregulates hepatocyte SR-BI showing that increased MAPK activity contributes to low SR-BI. Sphingomyelin which is well described to regulate cholesterol metabolism is reduced in the liver and serum of the knock-out mice while the size of serum lipoproteins is not affected. Current data exclude a major function of these syntrophins in ABCA1 activity and insulin release but suggest a role in regulating glucose uptake, ERK and SR-BI levels, and sphingomyelin metabolism in obesity.

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“…By decreasing the fluidity of HDLs but enhancing the affinity for cholesterol, increases in the sphingomyelin content of HDLs have a complex effect on cholesterol efflux capacity. 28, 238 One study reported an inverse association between sphingomyelin in HDL and the presence of CAD in women. 239 Because of their cytoprotective activities, S1P and other lysosphingolipids are especially interesting candidates to explain HDL dysfunction and to be used as underlying biomarkers.…”

Section: Post-translational Modifications Of Proteinsmentioning

confidence: 99%

High-Density Lipoproteins

Annema

Eckardstein

2013

Circ J

144

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary artery disease (CAD). HDL particles exert many effects in vitro and in vivo that may protect arteries from chemical or biological harm or facilitate repair of injuries. Nevertheless, HDL has not yet been successfully exploited for therapy. One potential reason for this shortfall is the structural and functional complexity of HDL particles, which carry more than 80 different proteins and more than 200 lipid species as well as several microRNAs and other potentially bioactive molecules. This physiological heterogeneity is further increased in several inflammatory conditions that increase cardiovascular risk, including CAD itself but also diabetes mellitus, chronic kidney disease, and rheumatic diseases. The quantitative and qualitative modifications of the proteome and lipidome, as well as the resulting loss of functions or gain of dysfunctions, are not recovered by the biomarker HDL-cholesterol. As yet the relative importance of the many physiological and pathological activities of normal and dysfunctional HDL, respectively, for the pathogenesis of atherosclerosis is unknown. The answer to this question, as well as detailed knowledge of structure-function-relationships of HDL-associated molecules, is a prerequisite to exploit HDL for the development of anti-atherogenic drugs as well as of diagnostic biomarkers for the identification, personalized treatment stratification, and monitoring of patients at increased cardiovascular risk. 2433Multifunctional but Vulnerable HDL munication of results. 15 As yet, clinical and epidemiological studies have come to discrepant and inconsistent conclusions on the prognostic performance of HDL subclasses differentiated by size. 14,20-24 Sometimes the associations of cardiovascular risk with the various HDL subclass concentrations were not stronger than with HDL-C, 20,21 and even if so, the associations with size were discrepant: significant associations with risk of cardiovascular events or stroke were found for small HDL in some studies, 22,23 but for medium-sized HDL 21,23 or large HDL 14,20,21,24 in others.Previous proteomic, lipidomic, and transcriptomic studies revealed a much greater structural complexity of HDLs: 80 different proteins, 25,26 more than 200 lipid species, 27,28 and several microRNAs 29,30 have been identified in HDL isolated from plasma by either ultracentrifugation, gel filtration, or immunoaffinity chromatography (Figure 1). Among the proteins, apoA-II is present in HDLs at the highest concentration after that of apoA-I and has been investigated for its cardiovascular risk association by several studies. In contrast to initial findings, large prospective studies did not find any significant differences in the risk association between apoA-II-containing and apoA-II-free HDL. [15][16][17] Despite their much lower concentrations relative to the 2 major proteins apoA-I and apoA-II and relative to the major lipids, many quantitatively minor componen...

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Sphingomyelin in High-Density Lipoproteins: Structural Role and Biological Function

Cited by 67 publications

References 180 publications

Determinants of HDL Cholesterol Efflux Capacity after Virgin Olive Oil Ingestion: Interrelationships with Fluidity of HDL Monolayer

Determinants of HDL Cholesterol Efflux Capacity after Virgin Olive Oil Ingestion: Interrelationships with Fluidity of HDL Monolayer

Lipid abnormalities in alpha/beta2-syntrophin null mice are independent from ABCA1

High-Density Lipoproteins

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