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Metabolomics reveals impaired maturation of HDL particles in adolescents with hyperinsulinaemic androgen excess.

ABSTRACT: Hyperinsulinaemic androgen excess (HIAE) in prepubertal and pubertal girls usually precedes a broader pathological phenotype in adulthood that is associated with anovulatory infertility, metabolic syndrome and type 2 diabetes. The metabolic derangements that determine these long-term health risks remain to be clarified. Here we use NMR and MS-based metabolomics to show that serum levels of methionine sulfoxide in HIAE girls are an indicator of the degree of oxidation of methionine-148 residue in apolipoprotein-A1. Oxidation of apo-A1 in methionine-148, in turn, leads to an impaired maturation of high-density lipoproteins (HDL) that is reflected in a decline of large HDL particles. Notably, such metabolic alterations occur in the absence of impaired glucose tolerance, hyperglycemia and hypertriglyceridemia, and were partially restored after 18 months of treatment with a low-dose combination of pioglitazone, metformin and flutamide.

SUBMITTER: Samino S

PROVIDER: S-EPMC4477239 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Metabolomics reveals impaired maturation of HDL particles in adolescents with hyperinsulinaemic androgen excess.

Samino Sara S Vinaixa Maria M Díaz Marta M Beltran Antoni A Rodríguez Miguel A MA Mallol Roger R Heras Mercedes M Cabre Anna A Garcia Lorena L Canela Nuria N de Zegher Francis F Correig Xavier X Ibáñez Lourdes L Ibáñez Lourdes L Yanes Oscar O

Scientific reports 20150623

Hyperinsulinaemic androgen excess (HIAE) in prepubertal and pubertal girls usually precedes a broader pathological phenotype in adulthood that is associated with anovulatory infertility, metabolic syndrome and type 2 diabetes. The metabolic derangements that determine these long-term health risks remain to be clarified. Here we use NMR and MS-based metabolomics to show that serum levels of methionine sulfoxide in HIAE girls are an indicator of the degree of oxidation of methionine-148 residue in ...[more]

PMID: 26099471

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Project description:Recent clinical trials reported that increasing high-density lipoprotein-cholesterol (HDL-C) levels does not improve cardiovascular outcomes. We hypothesize that HDL proteome dynamics determine HDL cardioprotective functions. In this study, we characterized proteome profiles in HDL subclasses and established their functional connection. Mouse plasma was fractionized by fast protein liquid chromatography, examined for protein, cholesterial, phospholipid and trigliceride content. Small, medium and large (S/M/L)-HDL subclasseses were collected for proteomic analysis by mass spectrometry. Fifty-one HDL proteins (39 in S-HDL, 27 in M-HDL and 29 in L-HDL) were identified and grouped into 4 functional categories (lipid metabolism, immune response, coagulation, and others). Eleven HDL common proteins were identified in all HDL subclasses. Sixteen, 3 and 7 proteins were found only in S-HDL, M-HDL and L-HDL, respectively. We established HDL protein dynamic distribution in S/M/L-HDL and developed a model of protein composition change during HDL maturation. We found that cholesterol efflux and immune response are essential functions for all HDL particles, and amino acid metabolism is a special function of S-HDL, whereas anti-coagulation is special for M-HDL. Pon1 is recruited into M/L-HDL to provide its antioxidative function. ApoE is incorporated into L-HDL to optimize its cholesterial clearance function. Next, we acquired HDL proteome data from Pubmed and identified 12 replicated proteins in human and mouse HDL particle. Finally, we extracted 3 shared top moleccular pathways (LXR/RXR, FXR/RXR and acute phase response) for all HDL particles and 5 top disease/bio-functions differentially related to S/M/L-HDL subclasses, and presented one top net works for each HDL subclass. We conclude that beside their essencial functions of cholesterol efflux and immune response, HDL aquired antioxidative and cholesterol clearance functions by recruiting Pon1 and ApoE during HDL maturation.

Project description:High-density lipoprotein (HDL), best known for cholesterol transport, also has anti-inflammatory effects. Previous studies suggest involvement of myeloperoxidase (MPO) in modification of HDL. HDL bound Sphingosine-1-phosphate (S1P) has been implied to be an essential protein regarding beneficial HDL effects. In this study, we analyzed anti-inflammatory HDL properties in patients with atrial fibrillation (AF), a disease involving atrial inflammation, compared to non-AF controls and whether anti-inflammatory properties improve upon catheter ablation. Additionally, association with serum concentrations of MPO and S1P were assessed. We isolated HDL from 25 AF patients, 13 non-AF individuals and 14 AF patients at follow-up (FU) after catheter ablation. S1P was measured in a cohort of 141 AF and 21 FU patients. Following preincubation with HDL from either group, bovine aortic endothelial cells were stimulated using tumor necrosis factor α and expression of pro-inflammatory genes intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), E-selectin (SELE) and P-selectin (SELP) was assessed using qPCR. Concentrations of circulating protein of these genes as well as MPO and S1P were measured in serum samples. Compared to non-AF individuals HDL from AF patients suppressed gene expression of the pro-inflammatory adhesion molecules ICAM1, VCAM1, SELE and SELP 27%, 18%, 21% and 57% less, respectively (p < 0.05 for all except SELE p = 0.06). In FU patients, the anti-inflammatory HDL activity was improved (suppression of ICAM1 + 22%, VCAM1 + 10%, SELE + 38% and SELP + 75%, p < 0.05 for all except VCAM1 p = 0.08). AF patients using angiotensin converting enzyme inhibitors or angiotensin receptor blockers had better anti-inflammatory HDL properties than non-users (gene expression suppression at least 28% more, p < 0.05 for all except ICAM1 p = 0.051). Circulating protein concentrations were not correlated with in vitro gene-expression, but circulating P-selectin was generally elevated in AF and FU patients compared to non-AF patients. MPO plasma concentration was positively associated with gene-expression of ICAM1, VCAM1 and SELP (r2 > 0.4, p < 0.05). Serum concentrations of S1P were increased in FU patients {1.201 µM [1.077-1.543]} compared to AF patients {0.953 µM [0.807-1.135], p < 0.01} but not correlated with ICAM1, VCAM1 and SELP gene expression. We conclude that the anti-inflammatory activity of HDL is impaired in AF patients, which might promote AF progression and AF-associated complications.

Dataset Information

Metabolomics reveals impaired maturation of HDL particles in adolescents with hyperinsulinaemic androgen excess.

Publications

Metabolomics reveals impaired maturation of HDL particles in adolescents with hyperinsulinaemic androgen excess.

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