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

Samino S, Vinaixa M, Díaz M, Beltran A, Rodríguez MA, Mallol R, Heras M, Cabre A, Garcia L, Canela N, de Zegher F, Correig X, Ibáñez L, Yanes O - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1] Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), C/ Monforte de Lemos 3-5, 28029 Madrid, Spain [2] Centre for Omic Sciences (COS), Rovira i Virgili University, Avinguda Universitat 3, 43204 Reus, Spain.

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.

No MeSH data available.


Related in: MedlinePlus

Oxidation of Apo-A1 and correlation of measurements.(A) Ratio of MetOx-148/Met-148 in apo-A1 (P < 0.05) measured by MALDI-TOF MS from the intensity of peptide K.LSPLGEEMR.D. (B) Statistically significant positive correlation (P = 6.95E-05 and r = 0.8) between free methionine sulfoxide in serum, as measured by LC-QqQ MS, and the oxidation state of apo-A1. (C) Statistically significant negative correlation (P = 1.13E-03 and r = −0.7) between free levels of methionine sulfoxide in serum and the percentage of large HDL particles, as measured by NMR. Controls are depicted in red and HIAE in blue.
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f4: Oxidation of Apo-A1 and correlation of measurements.(A) Ratio of MetOx-148/Met-148 in apo-A1 (P < 0.05) measured by MALDI-TOF MS from the intensity of peptide K.LSPLGEEMR.D. (B) Statistically significant positive correlation (P = 6.95E-05 and r = 0.8) between free methionine sulfoxide in serum, as measured by LC-QqQ MS, and the oxidation state of apo-A1. (C) Statistically significant negative correlation (P = 1.13E-03 and r = −0.7) between free levels of methionine sulfoxide in serum and the percentage of large HDL particles, as measured by NMR. Controls are depicted in red and HIAE in blue.

Mentions: The ratio MetOx-148/Met-148 in apo-A1 was significantly increased in HIAE girls compared with healthy controls (Fig. 4A). Furthermore, we found a positive and significant correlation (p = 6.95E-05 and r = 0.8) between the ratio MetOx-148/Met-148 in apo-A1 and free methionine sulfoxide in serum (Fig. 4B). Levels of methionine sulfoxide in serum, therefore, correlate with the degree of oxidation of the Met-148 residue in apo-A1, which may reflect turnover and proteolytic degradation of apo-A1 proteins. Finally, we found a negative correlation (p = 1.13E-03 and r = −0.7) between the number of large (i.e., mature) HDL particles and methionine sulfoxide in serum (Fig. 4C), which reinforces our hypothesis that levels of methionine sulfoxide in serum reflect HDL oxidation, and indirectly, impaired maturation of HDL particles.


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

Samino S, Vinaixa M, Díaz M, Beltran A, Rodríguez MA, Mallol R, Heras M, Cabre A, Garcia L, Canela N, de Zegher F, Correig X, Ibáñez L, Yanes O - Sci Rep (2015)

Oxidation of Apo-A1 and correlation of measurements.(A) Ratio of MetOx-148/Met-148 in apo-A1 (P < 0.05) measured by MALDI-TOF MS from the intensity of peptide K.LSPLGEEMR.D. (B) Statistically significant positive correlation (P = 6.95E-05 and r = 0.8) between free methionine sulfoxide in serum, as measured by LC-QqQ MS, and the oxidation state of apo-A1. (C) Statistically significant negative correlation (P = 1.13E-03 and r = −0.7) between free levels of methionine sulfoxide in serum and the percentage of large HDL particles, as measured by NMR. Controls are depicted in red and HIAE in blue.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4477239&req=5

f4: Oxidation of Apo-A1 and correlation of measurements.(A) Ratio of MetOx-148/Met-148 in apo-A1 (P < 0.05) measured by MALDI-TOF MS from the intensity of peptide K.LSPLGEEMR.D. (B) Statistically significant positive correlation (P = 6.95E-05 and r = 0.8) between free methionine sulfoxide in serum, as measured by LC-QqQ MS, and the oxidation state of apo-A1. (C) Statistically significant negative correlation (P = 1.13E-03 and r = −0.7) between free levels of methionine sulfoxide in serum and the percentage of large HDL particles, as measured by NMR. Controls are depicted in red and HIAE in blue.
Mentions: The ratio MetOx-148/Met-148 in apo-A1 was significantly increased in HIAE girls compared with healthy controls (Fig. 4A). Furthermore, we found a positive and significant correlation (p = 6.95E-05 and r = 0.8) between the ratio MetOx-148/Met-148 in apo-A1 and free methionine sulfoxide in serum (Fig. 4B). Levels of methionine sulfoxide in serum, therefore, correlate with the degree of oxidation of the Met-148 residue in apo-A1, which may reflect turnover and proteolytic degradation of apo-A1 proteins. Finally, we found a negative correlation (p = 1.13E-03 and r = −0.7) between the number of large (i.e., mature) HDL particles and methionine sulfoxide in serum (Fig. 4C), which reinforces our hypothesis that levels of methionine sulfoxide in serum reflect HDL oxidation, and indirectly, impaired maturation of HDL particles.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1] Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), C/ Monforte de Lemos 3-5, 28029 Madrid, Spain [2] Centre for Omic Sciences (COS), Rovira i Virgili University, Avinguda Universitat 3, 43204 Reus, Spain.

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.

No MeSH data available.


Related in: MedlinePlus