Apolipoprotein C-III isoforms: kinetics and relative implication in lipid metabolism

Abstract

Apolipoprotein C-III (apoC-III) production rate (PR) is strongly correlated with plasma triglyceride (TG) levels. ApoC-III exists in three different isoforms, according to the sialylation degree of the protein. We investigated the kinetics and respective role of each apoC-III isoform in modulating intravascular lipid/lipoprotein metabolism. ApoC-III kinetics were measured in a sample of 18 healthy men [mean age (6SD) 42.1 6 9.5 years, body mass index 29.8 6 4.6 kg/m 2 ] using a primed-constant infusion of L-(5,5,5-D3) leucine for 12 h. Mono-sialylated and di-sialylated apoC-III (apo-CIII 1 and apoC-III 2 ) exhibited similar PRs (means 6 SD, 1.22 6 0.49 mg/kg/day vs. 1.15 6 0.59 mg/ kg/day, respectively) and similar fractional catabolic rates (FCRs) (0.51 6 0.13 pool/day vs. 0.61 6 0.24 pool/day, respectively). Nonsialylated apoC-III (apoC-III 0 ) had an 80% lower PR (0.25 6 0.12 mg/kg/day) and a 60% lower FCR (0.21 6 0.07 pool/day) (P , 0.0001 for comparison with CIII 1 and CIII 2 isoforms). The PRs of apoC-III 1 and apoC-III 2 were more strongly correlated with plasma TG levels (r . 0.8, P , 0.0001) than was apoC-III 0 PR (r 5 0.54, P , 0.05). Finally, the PR of apoC-III 2 was strongly correlated with the proportion of LDL ,255 Å (r 5 0.72, P 5 0.002). These results suggest that all apoC-III isoforms, especially the predominant CIII 1 and CIII 2 isoforms, contribute to hypertriglyceridemia and that apoC-III 2 may play a significant role in the expression of the small, dense LDL phenotype.-Mauger J-F., P. Couture, N. Bergeron, and B. Lamarche. Apolipoprotein C-III isoforms: kinetics and relative implication in lipid metabolism. J. Lipid Res. 2006Res. . 47: 1212Res. -1218 Supplementary key words VLDL metabolism . metabolic syndrome . triglycerides . LDL particle size . sialylation Emphasis is continuously put on plasma triglyceride (TG) levels as a key correlate of many features of the metabolic syndrome, such as abdominal obesity, type 2 diabetes, lower levels of anti-atherogenic HDL-cholesterol (HDL-C), and higher levels of triglyceride-rich lipoproteins (TRLs) (1-3). Increased concentrations of plasma triglycerides are also thought to promote the expression of the type B LDL phenotype, characterized by the predominant presence of more-atherogenic, small, dense LDL particles (4, 5). In that context, there is a renewed interest in better understanding the mechanisms modulating plasma TG levels.Apolipoprotein C-III (apoC-III) is a protein secreted mostly by the liver and, to a lesser extent, by the intestine (3). In circulation, it is associated with both TRLs and HDL (6). ApoC-III is present in three isoforms that are termed apoC-III 0 , apoC-III 1 , and apoC-III 2 , depending on the number of sialic acid molecules (0 to 2) terminating the oligosaccharidic portions of the protein (7). Each isoform has been shown to contribute, respectively, to approximately 10, 55, and 35% of the total apoC-III levels in circulation (8). Total plasma apoC-III levels have been identified as a major determinant of trig...

Structure of HDL: Particle Subclasses and Molecular Components

“…This is then linked to reduced inhibition of lipoprotein lipase and improved triglyceride clearance. In line, the production rate of apoC-III 1 and -III 2 is more strongly correlated with plasma triglyceride levels than apoC-III 0 (Mauger et al 2006), increased apoC-III 1 / apoC-III 0 ratio has been found in diabetic subjects (Jian et al 2013), and HDL3 from subjects with low HDL-C is characterised by higher levels of monosialylated apoC-III than subjects with high HDL-C (Mazur et al 2010). The evaluation of apoC-III isoforms is complicated by the fact that apoC-III 0 can be separated into a non-glycosylated form and glycosylated but non-sialylated forms (Bruneel et al 2008;Holleboom et al 2011;Nicolardi et al 2013a).…”

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

“…This type of analysis has previously been limited by the time- and labor-intensive nature of the isoelectric focusing methodology that was used in previous studies. In two earlier small cross-sectional studies, the concentrations of sialylated apoC-III proteoforms in triglyceride-rich lipoproteins and their production rates correlated more strongly with plasma triglycerides than apoC-III 0 (22,26). The production rate of apoC-III 2 also negatively correlated with LDL peak particle size (26).…”

“…In two earlier small cross-sectional studies, the concentrations of sialylated apoC-III proteoforms in triglyceride-rich lipoproteins and their production rates correlated more strongly with plasma triglycerides than apoC-III 0 (22,26). The production rate of apoC-III 2 also negatively correlated with LDL peak particle size (26). However, in both studies, the regression slopes between apoC-III proteoforms and plasma triglycerides were greater for apoC-III 1 than for apoC-III 2 , indicating a less harmful relationship cholesterol-lowering agents (39).…”

“…apoC-III proteoforms show substantial functional differences in regulating cellular VLDL uptake in vitro (25). The few small studies in humans also indicate distinct effects of major apoC-III proteoforms on metabolic phenotypes (12,22,26). The scarcity of available data characterizing relationships between apoC-III proteoforms and human lipid phenotypes is partly explained by the limitations of using the relatively labor intensive isoelectric focusing approach for studies in larger cohorts.…”

Complexities of plasma apolipoprotein C-III metabolism

“…One additional reason to question the simplicity of a one-pool model of plasma apoC-III metabolism is that apoC-III exists as three isoforms, i.e., apoC-III 0 , apoC-III 1 and apoC-III 2 , corresponding to 0-2 sialic acid molecules on the protein. The isoform with most sialic acid, apoC-III 2 , tends to have a higher FCR compared with monosialylated apoC-III 1 , and apoC-III 0 , the less-predominant isoform, has a signifi cantly slower FCR and lower production rate s compared with the other two isoforms ( 32 ). These data suggest heterogeneity among apoC-III isoforms, regarding both secretion and clearance, which should be taken into consideration when dealing with disease conditions that directly affect apoC-III sialyation, including chronic renal failure ( 33 ).…”