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

Date Published: December 3, 2015

Publisher: Public Library of Science

Author(s): Hussein N. Yassine, Olgica Trenchevska, Ambika Ramrakhiani, Aarushi Parekh, Juraj Koska, Ryan W. Walker, Dean Billheimer, Peter D. Reaven, Frances T. Yen, Randall W. Nelson, Michael I. Goran, Dobrin Nedelkov, Yingmei Feng.


Apolipoprotein 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.

In 204 non-diabetic adolescent participants, the relative abundance of apoC-III plasma proteoforms was measured using mass spectrometric immunoassay.

Compared 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. We 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.

Partial Text

Apolipoprotein C-III (apoC-III) is a protein of 79 amino acids that is synthesized in the liver and, to a lesser degree in the intestine, and regulates triglyceride (TG) metabolism [1]. It is primarily located on the surface of lipoproteins [2]. In the circulation, apoC-III is a constituent of both apoB and apoA-I containing lipoproteins. The majority of apoC-III is found on the HDL fraction in normolipidemic individuals and on triglyceride-rich lipoproteins in patients with elevated levels of plasma triglyceride [3]. ApoC-III plays a pivotal role in regulating the plasma metabolism of VLDL, IDL, and LDL, primarily by inhibiting receptor-mediated uptake of these lipoproteins by the liver [4]. Overexpression of apoC-III in transgenic mice leads to severely increased plasma TG levels [5]. Mutations that disrupt apoC-III expression and function in humans are associated with lower plasma TG and apoC-III levels, and lower risk of coronary artery disease [6].

The study participants were predominantly overweight and obese Hispanic adolescents with a BMI z-score between– 0.98 and 3.1, and fasting plasma TG levels ranging from 19 to 330 mg/dL. None of the recruited participants had been diagnosed with diabetes, nor were on diabetes or lipid-lowering therapies. The mean fasting glucose among the participants was 92 mg/dL. With the exception of fasting insulin, the characteristics of the study participants did not differ by sex. Additional clinical and biochemical characteristics are summarized in Table 1.

ApoC-III in the plasma circulates predominantly as a sialylated apolipoprotein containing one or two molecules of sialic acid. ApoC-III is a key regulator of TG metabolism; however, the roles of the individual apoC-III proteoforms are not well understood. In the present study, we found that overweight and obese individuals had greater ratios of apoC-III0 or apoC-III1 proteoforms to apoC-III2 compared with leaner individuals. These ratios negatively correlated with insulin sensitivity (Si) and positively correlated with TG concentrations. Concentrations of apoC-III0a, apoC-III0b and apoC-III1, but not apoC-III2, correlated with fasting TG. These findings indicate that apoC-III0 and apoC-III1 are under metabolic control with a potential role for decreased insulin sensitivity in their formation, independent of changes in obesity. Our findings indicate that apoC-III2’s effects on TG metabolism differ from the other apoC-III proteoforms.