Apo CIII Proteoforms, Plasma Lipids, and Cardiovascular Risk in MESA

Abstract

Background: ApoC-III is an important regulator of triglyceride metabolism and was associated with cardiovascular risk in several cohorts. ApoC-III is present in 4 major proteoforms, a native peptide (C-III 0a ), and glycosylated proteoforms with zero (C-III 0b ), 1 (C-III 1 , most abundant), or 2 (C-III 2 ) sialic acids, which may differentially modify lipoprotein metabolism. We studied the relationships of these proteoforms with plasma lipids and cardiovascular risk. Methods: ApoC-III proteoforms were measured by mass spectrometry immunoassay in baseline plasma samples of 5791 participants of Multi-Ethnic Study of Atherosclerosis, an observational community-based cohort. Standard plasma lipids were collected for up to 16 years and cardiovascular events (myocardial infarction, resuscitated cardiac arrest, or stroke) were adjudicated for up to 17 years. Results: ApoC-III proteoform composition differed by age, gender, race and ethnicity, body mass index, and fasting glucose. Notably, C-III 1 was lower in older participants, men and Blacks and Chinese (versus Whites), and higher in obesity and diabetes. In contrast, C-III 2 was higher in older participants, men, Blacks, and Chinese, and lower in Hispanics and obesity. Higher C-III 2 to C-III 1 ratio (C-III 2 /III 1 ) was associated with lower triglycerides and higher HDL (high-density lipoprotein) in cross-sectional and longitudinal models, independently of clinical and demographic risk factors and total apoC-III. The associations of C-III 0a /III 1 and C-III 0b /III 1 with plasma lipids were weaker and varied through cross-sectional and longitudinal analyses. Total apoC-III and C-III 2 /III 1 were positively associated with cardiovascular disease risk (n=669 events, hazard ratios, 1.14 [95% CI, 1.04–1.25] and 1.21 [1.11–1.31], respectively); however, the associations were attenuated after adjustment for clinical and demographic characteristics (1.07 [0.98–1.16]; 1.07 [0.97–1.17]). In contrast, C-III 0b /III 1 was inversely associated with cardiovascular disease risk even after full adjustment including plasma lipids (0.86 [0.79–0.93]). Conclusions: Our data indicate differences in clinical and demographic relationships of apoC-III proteoforms, and highlight the importance of apoC-III proteoform composition in predicting future lipid patterns and cardiovascular disease risk.

Triglyceride-Rich Lipoprotein Metabolism: Key Regulators of Their Flux

“…New targets, blocking inhibitors of LPLs [ 10 , 28 , 33 , 97 , 98 , 99 ]. In lipid-lowering medications over the past five years, attention has been placed on developing substances that boost TRL lipolysis.…”

Apolipoprotein C3: form begets function

“…In addition to the pools of APOC3 carried by different lipoproteins, APOC3 exists in several distinct glycoforms, glycosylated at Thr74 in human plasma. The most relevant glycoforms are the native APOC3 0a and three O-glycosylated forms: APOC3 0b , with one galactose and one N-galactosamine (GalNAc); APOC3 1 with one sialic acid added to the galactose and GalNAc and APOC3 2 , with two sialic acid residues added to the APOC3 0b form ( 38 , 39 ) ( Fig. 1 ).…”

“…1 ). Of those, APOC3 1 is most abundant in plasma and in all lipoproteins, although there is significant variability between individuals ( 38 ) and with race and ethnicity ( 39 ). The APOC3 1 proteoform was more abundant in people with diabetes and obesity in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort ( 39 ).…”

“…Of those, APOC3 1 is most abundant in plasma and in all lipoproteins, although there is significant variability between individuals ( 38 ) and with race and ethnicity ( 39 ). The APOC3 1 proteoform was more abundant in people with diabetes and obesity in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort ( 39 ). Importantly, the ratio of APOC3 0b /APOC3 1 was negatively associated with CVD risk after full adjustment in models including plasma triglycerides, HDL-cholesterol, and total APOC3 levels ( 39 ).…”

“…The APOC3 1 proteoform was more abundant in people with diabetes and obesity in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort ( 39 ). Importantly, the ratio of APOC3 0b /APOC3 1 was negatively associated with CVD risk after full adjustment in models including plasma triglycerides, HDL-cholesterol, and total APOC3 levels ( 39 ). The role of the APOC3 0b proteoform is interesting because this form did not show a strong association with traditional CVD risk factors, including lipids.…”