Sialylated isoforms of apolipoprotein C-III and plasma lipids in subjects with coronary artery disease

Olivieri, Oliviero; Chiariello, Carmela; Martinelli, Nicola; Castagna, Annalisa; Speziali, Giulia; Girelli, Domenico; Pizzolo, Francesca; Bassi, Antonella; Cecconi, Daniela; Robotti, Elisa; Manfredi, Marcello; Conte, Eleonora; Marengo, Emílio

doi:10.1515/cclm-2017-1099

Cited by 12 publications

(13 citation statements)

References 33 publications

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“…However, no other significant correlations were found among the analyzed proteoforms. Our results are consistent with those reported by Olivieri et al in a cohort of CAD patients where a negative tendency was reported between Apo CIII0 proteoforms and TG (34).…”

Section: Discussionsupporting

confidence: 94%

Lipoprotein distribution of Apo CIII glycoforms in healthy men is linked with low TG and increased insulin sensitivity

Rodríguez

Rehues

Iranzo

et al. 2020

Preprint

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Glycosylation of Apo CIII modulates its function in triglyceride metabolism, and some variants are associated with a protective or pro-atherogenic lipid profile. These associations have been studied in whole plasma Apo CIII proteoforms, but the proportion of Apo CIII proteoforms in individual lipoprotein fractions has been rarely evaluated. In the present study, we aim to measure the relative content of Apo CIII proteoforms in each lipoprotein fraction (VLDL, IDL, LDL and HDL) in a group of healthy subjects as a potential biomarker for triglyceride metabolism, cardiovascular risk and diabetes. Lipoprotein fractions were separated by differential ultracentrifugation of plasma samples. The relative concentrations of seven Apo CIII variants were measured by mass spectrometric immunoassay, and the complete lipoprotein profile was determined by NMR. The results showed high interindividual variability in the distribution of Apo CIII proteoforms across the study population but a uniform proportion in all lipoprotein fractions. Two Apo CIII variants, Apo CIII0b and Apo CIII1d, were negatively correlated with plasma and VLDL triglycerides regardless of VLDL size and were associated with increased LDL size when transported in LDL particles. Apo CIII0b also showed a negative correlation with lipoprotein-insulin resistance score. Therefore, Apo CIII variants can be reliably measured in lipoprotein fractions, and our results suggest that Apo CIII0b and Apo CIII1d have a protective role in triglyceride metabolism and insulin resistance in healthy individuals.

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Section: Discussionsupporting

confidence: 94%

Lipoprotein distribution of Apo CIII glycoforms in healthy men is linked with low TG and increased insulin sensitivity

Rodríguez

Rehues

Iranzo

et al. 2020

Preprint

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“…The physiological relevance of these glycoforms is still unclear, but the degree of sialylation of apoC-III has been proposed to influence lipoprotein lipase (LPL)-mediated hydrolysis of TRLs in the circulation. Recent investigations reveal that the different apoC-III glycoforms show specific patterns over the range of total apoC-III concentration, but the impact of this variation on the atherogenic potential of the apoprotein is unclear [ 7 •].…”

Section: Introductionmentioning

confidence: 99%

Emerging Evidence that ApoC-III Inhibitors Provide Novel Options to Reduce the Residual CVD

Taskinen

Packard

Borén

2019

Curr Atheroscler Rep

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Purpose of Review Apolipoprotein C-III (apoC-III) is known to inhibit lipoprotein lipase (LPL) and function as an important regulator of triglyceride metabolism. In addition, apoC-III has also more recently been identified as an important risk factor for cardiovascular disease. This review summarizes the mechanisms by which apoC-III induces hypertriglyceridemia and promotes atherogenesis, as well as the findings from recent clinical trials using novel strategies for lowering apoC-III. Recent Findings Genetic studies have identified subjects with heterozygote loss-of-function (LOF) mutations in APOC3, the gene coding for apoC-III. Clinical characterization of these individuals shows that the LOF variants associate with a low-risk lipoprotein profile, in particular reduced plasma triglycerides. Recent results also show that complete deficiency of apoC-III is not a lethal mutation and is associated with very rapid lipolysis of plasma triglyceride-rich lipoproteins (TRL). Ongoing trials based on emerging gene-silencing technologies show that intervention markedly lowers apoC-III levels and, consequently, plasma triglyceride. Unexpectedly, the evidence points to apoC-III not only inhibiting LPL activity but also suppressing removal of TRLs by LPL-independent pathways. Summary Available data clearly show that apoC-III is an important cardiovascular risk factor and that lifelong deficiency of apoC-III is cardioprotective. Novel therapies have been developed, and results from recent clinical trials indicate that effective reduction of plasma triglycerides by inhibition of apoC-III might be a promising strategy in management of severe hypertriglyceridemia and, more generally, a novel approach to CHD prevention in those with elevated plasma triglyceride.

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“…The application of more specific enrichment methods, such as immunocapture, may help to reduce signals interfering with the various apo-CIII oxidoforms, but was not implemented in the present study for simplicity reasons. Of note, apo-CIII proteoforms have been analyzed by methods employing LC systems (Kailemia et al, 2018;Olivieri et al, 2018). Despite certain advantages over MALDI-TOF MS, such as absolute quantification and enhanced resolution, the throughput of this approach remains relatively low.…”

Section: Resultsmentioning

confidence: 99%

“…Expression levels of apo-CIII were not investigated in this study. The differences in apo-CIII glycosylation profiles observed between individuals may be caused by varying expression levels of apo-CIII (Olivieri et al, 2018) or apo-CIII glycoforms (Holleboom et al, 2011), or the accumulation of certain glycoforms due to dysfunctional clearance pathways, based on recent findings by Kegulian et al (Kegulian et al, 2019). It may also be a combination of the listed factors, which should be explored in further research.…”

Section: Associations Between Apo-ciii Sialylation and Lipid Markersmentioning

confidence: 98%

“…So far, the inhibitory effect of apo-CIII on LPL has been linked to total apo-CIII concentration, but not to the relative proportion of apo-CIII glycoforms (Olivieri et al, 2018). Recent studies proposed that the presence of apo-CIII on triglyceride-rich lipoproteins (TRLs) alters the affinity between TRLs and their receptors in the liver.…”

Section: Associations Between Apo-ciii Sialylation and Lipid Markersmentioning

confidence: 99%

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Large-Scale Analysis of Apolipoprotein CIII Glycosylation by Ultrahigh Resolution Mass Spectrometry

et al. 2021

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Apolipoprotein-CIII (apo-CIII) is a glycoprotein involved in lipid metabolism and its levels are associated with cardiovascular disease risk. Apo-CIII sialylation is associated with improved plasma triglyceride levels and its glycosylation may have an effect on the clearance of triglyceride-rich lipoproteins by directing these particles to different metabolic pathways. Large-scale sample cohort studies are required to fully elucidate the role of apo-CIII glycosylation in lipid metabolism and associated cardiovascular disease. In this study, we revisited a high-throughput workflow for the analysis of intact apo-CIII by ultrahigh-resolution MALDI FT-ICR MS. The workflow includes a chemical oxidation step to reduce methionine oxidation heterogeneity and spectrum complexity. Sinapinic acid matrix was used to minimize the loss of sialic acids upon MALDI. MassyTools software was used to standardize and automate MS data processing and quality control. This method was applied on 771 plasma samples from individuals without diabetes allowing for an evaluation of the expression levels of apo-CIII glycoforms against a panel of lipid biomarkers demonstrating the validity of the method. Our study supports the hypothesis that triglyceride clearance may be regulated, or at least strongly influenced by apo-CIII sialylation. Interestingly, the association of apo-CIII glycoforms with triglyceride levels was found to be largely independent of body mass index. Due to its precision and throughput, the new workflow will allow studying the role of apo-CIII in the regulation of lipid metabolism in various disease settings.

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Sialylated isoforms of apolipoprotein C-III and plasma lipids in subjects with coronary artery disease

Abstract: Specific patterns of ApoC-III glycoforms are present across different total ApoC-III concentrations in CAD patients. The inhibitory effect of ApoC-III on LPL appears related to total ApoC-III concentration, but not to the relative proportion of ApoC-III glycoforms.

Cited by 12 publications

References 33 publications

Lipoprotein distribution of Apo CIII glycoforms in healthy men is linked with low TG and increased insulin sensitivity

Lipoprotein distribution of Apo CIII glycoforms in healthy men is linked with low TG and increased insulin sensitivity

Emerging Evidence that ApoC-III Inhibitors Provide Novel Options to Reduce the Residual CVD

Large-Scale Analysis of Apolipoprotein CIII Glycosylation by Ultrahigh Resolution Mass Spectrometry

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