Disialylated apolipoprotein C-III proteoform is associated with improved lipids in prediabetes and type 2 diabetes

Koška, Juraj; Yassine, Hussein N.; Trenchevska, Olgica; Sinari, Shripad; Schwenke, Dawn C.; Yen, Frances T.; Billheimer, Dean; Nelson, Randall W.; Nedelkov, Dobrin; Reaven, Peter D.

doi:10.1194/jlr.p064816

Cited by 50 publications

(53 citation statements)

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“…The altered charge of apoC-III conferred by disialylation could impede its ability to compete against apoE for TRL particle binding, resulting in reduced inhibition of apoE-mediated delivery of TRL to receptors. We and others have demonstrated that apoC-III 2 is a less efficient inhibitor of VLDL cellular uptake compared with apoC-III 0 or apoCIII 1 on hepatic receptors ex vivo (18, 32). This is also demonstrated with sialylation of apoE enhancing the uptake of HDL in HepG2 cells (33).…”

Section: Discussionmentioning

confidence: 88%

“…Our findings demonstrate that changes of apoC-III 1 , apoC-III 0a and apoC-III 0b , but not apoC-III 2 were associated with changes in LDL peak particle diameter in both interventions. We have previously reported that apoC-III 1 apoC-III 0a and apoC-III 0b but not apoC-III 2 associate with fasting TG levels in a group of obese prediabetic individuals (15) and in patients with type II diabetes (18). We now demonstrate that these apoC-III glycoforms associate with the changes in small dense LDL using two interventions that promoted (high carb diet) or reversed (weight loss) small dense LDL phenotype.…”

Section: Discussionmentioning

confidence: 98%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 98%

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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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“…APOE4 status was defined by visible APOE4 bands after Western blotting of plasma samples. APOE plasma levels were measured using an in-house enzyme-linked immunosorbent assay with inter- and intraassay coefficients of variation <10% [25]. …”

Section: Methodsmentioning

confidence: 99%

DHA brain uptake and APOE4 status: a PET study with [1-11C]-DHA

et al. 2017

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BackgroundThe apolipoprotein E ɛ4 (APOE4) allele is the strongest genetic risk factor identified for developing Alzheimer’s disease (AD). Among brain lipids, alteration in the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) homeostasis is implicated in AD pathogenesis. APOE4 may influence both brain DHA metabolism and cognitive outcomes.MethodsUsing positron emission tomography, regional incorporation coefficients (k*), rates of DHA incorporation from plasma into the brain using [1-11C]-DHA (J in), and regional cerebral blood flow using [15O]-water were measured in 22 middle-aged healthy adults (mean age 35 years, range 19–65 years). Data were partially volume error-corrected for brain atrophy. APOE4 phenotype was determined by protein expression, and unesterified DHA concentrations were quantified in plasma. An exploratory post hoc analysis of the effect of APOE4 on DHA brain kinetics was performed.ResultsThe mean global gray matter DHA incorporation coefficient, k*, was significantly higher (16%) among APOE4 carriers (n = 9) than among noncarriers (n = 13, p = 0.046). Higher DHA incorporation coefficients were observed in several brain regions, particularly in the entorhinal subregion, an area affected early in AD pathogenesis. Cerebral blood flow, unesterified plasma DHA, and whole brain DHA incorporation rate (J in) did not differ significantly between the APOE groups.ConclusionsOur findings suggest an increase in the DHA incorporation coefficient in several brain regions in APOE4 carriers. These findings may contribute to understanding how APOE4 genotypes affect AD risk.

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“…[37] Interestingly, LDL desialylation is assumed to be a systemic process, which affects not only LDL as a single target. Recently Koska et al [38] have reported that properly glycosylated apoC-III proteoform (i.e. apoprotein-bearing 2 sialic acid residues per every biantennary polysaccharide chain), in contrast to partially or totally desialylated proteoforms, is associated with beneficial lipid profile in prediabetic and type 2 diabetic patients.…”

Section: Discussionmentioning

confidence: 99%

Small dense and desialylated low density lipoprotein in diabetic patients

Sobenin¹,

Galitsyna²,

Grechko³

et al. 2017

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How to cite this article: Sobenin IA, Galitsyna EV, Grechko AV, Orekhov AN. Small dense and desialylated low density lipoprotein in diabetic patients. Vessel Plus 2017;1:29-37.Aim: This study was undertaken to investigate the physicochemical properties of modified low density lipoprotein (LDL) in diabetes. Methods: LDL from 10 type 1 and 10 type 2 diabetic patients, as well as LDL from 10 non-diabetic subjects, was subdivided into bound and nonbound fractions by affinity chromatography on Ricinus communis agglutinin-agarose, and further characterized by sialic acid content, hydrated density, electrophoretic mobility, and the ability to induce cholesterol deposition in cultured cells. Results: The non-bound LDL fraction was similar to native LDL from healthy subjects, with respect to its physicochemical properties, and did not produce intracellular cholesterol accumulation. The bound LDL fraction was characterized by several alterations differentiating it from non-bound LDL, namely, significantly lowered sialic acid content (by 35-50%, compared with non-bound LDL), increased electrophoretic mobility (by 40-50%), increased hydrated density (difference in modae, 5.6-5.9 mg/mL), and smaller particle size (difference in modae, 3.8-4.9 nm). Bound LDL possessed the ability to induce a 2.1-to 2.7-fold increase in intracellular cholesterol content. Conclusion: The results showed the presence of a dense, small, more electronegative, desialylated LDL subfraction in the blood of diabetic patients, which is in vivo modified atherogenic LDL.

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Disialylated apolipoprotein C-III proteoform is associated with improved lipids in prediabetes and type 2 diabetes

Cited by 50 publications

References 56 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

DHA brain uptake and APOE4 status: a PET study with [1-11C]-DHA

Small dense and desialylated low density lipoprotein in diabetic patients

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