Background
Apolipoprotein (apo) C-III is involved in several processes that increase triglyceride levels, inflammation, and insulin resistance. Four of its proteoforms have been the focus of several studies and have shown differential associations with cardiovascular risk biomarkers, mostly lipids. However, there are other proteoforms of apoC-III that have not yet been investigated in detail. The aim of this study was to evaluate the associations of seven apoC-III proteoforms with a comprehensive set of biomarkers, including lipid metabolism, inflammation, and glucose homeostasis.
Methods
Seven apoC-III proteoforms (apoC-III
0a
, apoC-III
0b
, apoC-III
1
, apoC-III
1d
, apoC-III
2
, apoC-III
2d
, and apoC-III
0f
) were measured using a mass spectrometry immunoassay in 875 participants from the cross-sectional study of the Di@bet.es cohort. The complete lipoprotein profile was obtained via the Liposcale test, and the proton nuclear magnetic resonance (
1
H-NMR)-assessed glycoprotein signals were also obtained as biomarkers of inflammation.
Results
Three proteoform ratios (apoC-III
2d
, apoC-III
2
, and apoC-III
0f
normalized to apoC-III
1
) showed protective associations with most of the cardiovascular risk biomarkers in comparison with total apoC-III in linear regression models and were negatively associated with triglycerides (β=-0.173,
p
< 0.001; β=-0.297,
p
< 0.001; β=-0.223,
p
= 0.002), very low-density (VLDL) particle concentration (β=-0.133,
p
< 0.001; β=-0.265,
p
< 0.001; β=-0.203,
p
< 0.001), GlycA (β=-0.148,
p
< 0.001; β=-0.263,
p
< 0.001; β=-0.211,
p
< 0.001) and homeostatic model assessment of insulin resistance (HOMA-IR) (β=-0.096,
p
= 0.003; β=-0.199,
p
< 0.001; β=-0.114,
p
= 0.002). These associations were partly independent of total apoC-III concentrations. Participants with high levels of these proteoforms had a lower prevalence of cardiometabolic disorders, such as type 2 diabetes (
p
= 0.022), obesity (
p
= 0.001), and metabolic syndrome (
p
= 0.013).
Conclusions
While apoC-III is positively associated with biomarkers of cardiometabolic risk, the proportions of three apoC-III proteoforms show opposite associations, independent of total apoC-III concentrations. Measuring not onl...
