Reduced Apolipoprotein Glycosylation in Patients with the Metabolic Syndrome

Savinova, Olga V.; Fillaus, Kristi; Jing, Linhong; Harris, William S.; Shearer, Gregory C.

doi:10.1371/journal.pone.0104833

Cited by 42 publications

(49 citation statements)

References 64 publications

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“…In previous work, we reported an association of apoC-III 0 and apoC-III 1 , but not apoC-III 2 with fasting plasma triglyceride (TG) levels in a group of obese youth with high TG levels (15), and in the setting of type 2 diabetes(18). Decreased apoC-III 2 to apoC-III 1 ratio was also observed in adults with metabolic syndrome (19). The apoC-III 2 to apoC-III 1 ratio was reduced following weight loss by caloric restriction (20), or bariatric surgery (21).…”

Section: Introductionmentioning

confidence: 98%

Changes in low-density lipoprotein size phenotypes associate with changes in apolipoprotein C-III glycoforms after dietary interventions

Mendoza

Trenchevska

King³

et al. 2017

Journal of Clinical Lipidology

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Background The presence of small dense LDL is associated with obesity and type 2 diabetes and an increased risk for cardiovascular disease. Apolipoprotein C-III (apoC-III) is involved in the formation of small dense LDL, but the exact mechanisms are still not well defined. ApoC-III is a glycosylated apolipoprotein, with three major glycoforms: apoC-III0, apoC-III1, and apoC-III2 that contain zero, one, or two molecules of sialic acid, respectively. In our previous work, we reported an association among apoC-III0 and apoC-III1, but not apoC-III2 with fasting plasma triglyceride levels in obesity and type 2 diabetes. Objective The goal of this study was to determine the relationship between changes in the major apoC-III glycoforms and small dense LDL levels after dietary interventions. Methods Mass spectrometric immunoassay (MSIA) was performed on fasting plasma samples from 61 subjects who underwent either a high carbohydrate diet (n=34) or a weight loss intervention (n=27). Results After both dietary interventions, changes in total apoC-III concentrations were associated with changes in LDL peak particle diameter (r= −0.58, p<0.0001). Increases in total apoC-III concentrations following the high carbohydrate diet were associated with decreases in LDL size (r= −0.53, p=0.001), and decreases in apoC-III concentrations following weight loss were associated with increases in LDL peak particle diameter (r= −0.54, p=0.004). Changes in concentrations of apoC-III1 and apoC-III0, but not apoC-III2, were associated with changes in LDL peak particle diameter in both the weight loss and high carbohydrate interventions. Conclusion We conclude that apoC-III0 and apoC-III1, but not apoC-III2 are associated with the formation of small dense LDL.

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Section: Introductionmentioning

confidence: 98%

Changes in low-density lipoprotein size phenotypes associate with changes in apolipoprotein C-III glycoforms after dietary interventions

Mendoza

Trenchevska

King³

et al. 2017

Journal of Clinical Lipidology

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“…Another group has reported a similar finding. In HDL from patients with MetS both the amount of ApoC-III and SAA, and the glycosylation of ApoC-III, were altered compared to healthy controls23. Thus, it is becoming increasingly apparent that there is differential expression of the HDL glycoproteome in health and disease; however, little is known about how glycan alterations affect HDL function.…”

mentioning

confidence: 99%

HDL Glycoprotein Composition and Site-Specific Glycosylation Differentiates Between Clinical Groups and Affects IL-6 Secretion in Lipopolysaccharide-Stimulated Monocytes

Krishnan

Shimoda

Sacchi

et al. 2017

Sci Rep

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The goal of this pilot study was to determine whether HDL glycoprotein composition affects HDL’s immunomodulatory function. HDL were purified from healthy controls (n = 13), subjects with metabolic syndrome (MetS) (n = 13), and diabetic hemodialysis (HD) patients (n = 24). Concentrations of HDL-bound serum amyloid A (SAA), lipopolysaccharide binding protein (LBP), apolipoprotein A-I (ApoA-I), apolipoprotein C-III (ApoC-III), α-1-antitrypsin (A1AT), and α-2-HS-glycoprotein (A2HSG); and the site-specific glycovariations of ApoC-III, A1AT, and A2HSG were measured. Secretion of interleukin 6 (IL-6) in lipopolysaccharide-stimulated monocytes was used as a prototypical assay of HDL’s immunomodulatory capacity. HDL from HD patients were enriched in SAA, LBP, ApoC-III, di-sialylated ApoC-III (ApoC-III2) and desialylated A2HSG. HDL that increased IL-6 secretion were enriched in ApoC-III, di-sialylated glycans at multiple A1AT glycosylation sites and desialylated A2HSG, and depleted in mono-sialylated ApoC-III (ApoC-III1). Subgroup analysis on HD patients who experienced an infectious hospitalization event within 60 days (HD+) (n = 12), vs. those with no event (HD−) (n = 12) showed that HDL from HD+ patients were enriched in SAA but had lower levels of sialylation across glycoproteins. Our results demonstrate that HDL glycoprotein composition, including the site-specific glycosylation, differentiate between clinical groups, correlate with HDL’s immunomodulatory capacity, and may be predictive of HDL’s ability to protect from infection.

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“…Known risk factors for VTE, ie, factor V Leiden and prothrombin nt G20210A, were not associated with SAA4 levels. Since SAA4 is carried by lipoproteins, [17][18][19] the association of SAA4 levels with lipoprotein particle levels, that is, with factors that may reflect metabolism of lipoproteins (hormone use and obesity) was analyzed (Table 3). Among them, HDL particles levels were correlated with SAA4.…”

Section: Resultsmentioning

confidence: 99%

“…Constitutive SAA4, where “constitutive” denotes its level is not subject to remarkable alterations, is linked to a certain group of HDL particles (HDL 3 ) . More recent studies have identified a minor portion of SAA4 that is in the LDL and VLDL subfractions . SAA4 comprises >90% of the total serum SAA proteins in the absence of inflammatory pathologies with a serum concentration of 42 to 86 µg/mL, which is high in comparison with basal acute‐phase SAA (SAA1 plus SAA2) levels (average, 1‐2 µg/mL) .…”

Section: Introductionmentioning

confidence: 99%

“…17 More recent studies have identified a minor portion of SAA4 that is in the LDL and VLDL subfractions. 18,19 SAA4 comprises >90% of the total serum SAA proteins 17 in the absence of inflammatory pathologies with a serum concentration of 42 to 86 µg/mL, which is high in comparison with basal acute-phase SAA (SAA1 plus SAA2) levels (average, 1-2 µg/ mL). 9,12,13 SAA4 expression is implicated during inflammation including atherosclerosis; notably, SAA4 lacks expression in normal arteries but is expressed in carotid lesions.…”

Section: Introductionmentioning

confidence: 99%

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Serum amyloid A4 is a procoagulant apolipoprotein that it is elevated in venous thrombosis patients

Fernández

Deguchi

Elias

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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Background Serum amyloid A4 (SAA4) is an apolipoprotein that is in the SAA family and it is constitutively translated. Previously, acute‐phase SAA1 and SAA2 levels were associated with venous thromboembolism (VTE). Objective We investigated the association of plasma SAA4 with VTE and the role of SAA4 in coagulation. Patients and Methods The association of SAA4 with VTE in a case‐control study of adult VTE subjects (N = 113 each group) and the effects of recombinant SAA4 on plasma blood coagulation assays and prothrombin activation initiated by factor Xa were evaluated. Results Plasma SAA4 levels in VTE subjects were higher vs. controls (48.1 vs. 38.4 µg/mL; P < .001). Elevated plasma SAA4 level (above the 90th percentile of controls) was associated with increased VTE occurrence (odds ratio, 3.8; 95% confidence interval, 1.8‐8.0). This association remained significant after the adjustment for acute‐phase SAA level, suggesting that SAA4 associated with VTE is independent of acute‐phase SAA. Two isoforms of SAA4, that is, glycosylated and nonglycosylated SAA4 isoforms, were each higher in VTE patients. When recombinant SAA4 was added to plasma, it shortened factor Xa‐1‐stage clotting times, showing that it enhances clotting in plasma. In reaction mixtures containing purified factors Xa and Va and prothrombin, recombinant SAA4 increased prothrombin activation, showing that it enhances prothrombinase activity. Conclusion Elevated plasma constitutive SAA4 levels were linked to VTE in adults, and SAA4 can enhance thrombin generation in plasma. Our data highlight a previously unknown procoagulant activity of SAA4 that appears to be related to risk of venous thrombotic events.

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Reduced Apolipoprotein Glycosylation in Patients with the Metabolic Syndrome

Cited by 42 publications

References 64 publications

Changes in low-density lipoprotein size phenotypes associate with changes in apolipoprotein C-III glycoforms after dietary interventions

Changes in low-density lipoprotein size phenotypes associate with changes in apolipoprotein C-III glycoforms after dietary interventions

HDL Glycoprotein Composition and Site-Specific Glycosylation Differentiates Between Clinical Groups and Affects IL-6 Secretion in Lipopolysaccharide-Stimulated Monocytes

Serum amyloid A4 is a procoagulant apolipoprotein that it is elevated in venous thrombosis patients

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