The Association of Human Apolipoprotein C-III Sialylation Proteoforms with Plasma Triglycerides

Abstract

IntroductionApolipoprotein C-III (apoC-III) regulates triglyceride (TG) metabolism. In plasma, apoC-III exists in non-sialylated (apoC-III0a without glycosylation and apoC-III0b with glycosylation), monosialylated (apoC-III1) or disialylated (apoC-III2) proteoforms. Our aim was to clarify the relationship between apoC-III sialylation proteoforms with fasting plasma TG concentrations.MethodsIn 204 non-diabetic adolescent participants, the relative abundance of apoC-III plasma proteoforms was measured using mass spectrometric immunoassay.ResultsCompared with the healthy weight subgroup (n = 16), the ratios of apoC-III0a, apoC-III0b, and apoC-III1 to apoC-III2 were significantly greater in overweight (n = 33) and obese participants (n = 155). These ratios were positively correlated with BMI z-scores and negatively correlated with measures of insulin sensitivity (Si). The relationship of apoC-III1 / apoC-III2 with Si persisted after adjusting for BMI (p = 0.02). Fasting TG was correlated with the ratio of apoC-III0a / apoC-III2 (r = 0.47, p<0.001), apoC-III0b / apoC-III2 (r = 0.41, p<0.001), apoC-III1 / apoC-III2 (r = 0.43, p<0.001). By examining apoC-III concentrations, the association of apoC-III proteoforms with TG was driven by apoC-III0a (r = 0.57, p<0.001), apoC-III0b (r = 0.56. p<0.001) and apoC-III1 (r = 0.67, p<0.001), but not apoC-III2 (r = 0.006, p = 0.9) concentrations, indicating that apoC-III relationship with plasma TG differed in apoC-III2 compared with the other proteoforms.ConclusionWe conclude that apoC-III0a, apoC-III0b, and apoC-III1, but not apoC- III2 appear to be under metabolic control and associate with fasting plasma TG. Measurement of apoC-III proteoforms can offer insights into the biology of TG metabolism in obesity.

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

“…Importantly, the associations were very similar in the two current cohorts and our recently reported cross-sectional study (28), despite differences in their demographic and clinical characteristics (e.g., age, gender, ethnicity, glucose tolerance status, and prevalence of CVD). The association between relative apoC-III 2 abundance and triglycerides remained present after adjustment for relevant demographic factors and even lipid lowering medications, suggesting that apoC-III 2 abundance may be an independent determinant of plasma triglyceride levels.…”

“…This suggests the possibility of a PPAR- agonist class effect on apoC-III 2 , which could be related to their known triglyceride lowering action. The positive cross-sectional association of apoC-III 2 /apoC-III 1 with insulin sensitivity in our previous study (28) indicates that this effect may be related to the insulin-sensitizing action of PPAR- agonists. Second, the relative distribution of apoC-III proteoforms was modified by the use of lipid-lowering drugs, and there was evidence of proteoform-specific effects.…”

“…Plasma samples from overweight and obese youth participants in the University of Southern California Obesity Study (28) with either high (upper quartile) or low (lower quartile) apoC-III 2 / apoC-III 1 ratios were used to isolate VLDL and apoC-III complexes from the VLDL. These plasma samples for VLDL isolation were selected based on MSIAs performed on a total 72 available plasma samples.…”

“…University of Southern California Obesity Study (28). All studies were approved by the Institutional Review Boards of all study centers and all participants gave written informed consent.…”

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

“…These glycoforms differ by their sialic acid content in the glycan motif, having zero, one and two sialic acid residues correspondingly, attached to a glycan core of N-acetylgalactosamine (Gal-NAc) and galactose (Gal) (15). Sialylation occurs in the Golgi apparatus, and is mediated by a group of sialyltransferases, whereas lysosomal neuraminidase regulates the desialylation (16).…”