Plasma apolipoprotein C-III metabolism in patients with chronic kidney disease

Abstract

Supplementary key words kinetics • lipoprotein metabolism • triglyceridesCardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD) ( 1 ). While the precise mechanisms for increased CVD risk are unknown, both traditional and novel CVD risk factors have been implicated ( 1, 2 ). Dyslipidemia, a well-established risk factor for CVD in the general population, is highly prevalent in CKD ( 3, 4 ). The most frequent dyslipoproteinemic phenotype patterns are elevated plasma concentrations of triglycerides and increased numbers of atherogenic triglyceride-rich lipoprotein (TRL) particles, particularly VLDL and intermediate-density lipoprotein (IDL) ( 3, 4 ). The regulation of TRL metabolism in CKD, however, is poorly understood.Apolipoprotein C-III (apoC-III) is an 8.8 kDa glycoprotein synthesized by the liver and intestines ( 5 ). ApoC-III is highly associated with hypertriglyceridemia and is a powerful independent predictor of CVD risk in subjects without renal disease ( 5 ). In the circulation, apoC-III is associated with TRL and HDL exchanging rapidly between these lipoproteins ( 6 ). In vitro studies demonstrate that apoC-III Abstract Moderate chronic kidney disease (CKD) (defi ned by an estimated glomerular fi ltration rate of 30-60 ml/min) is associated with mild hypertriglyceridemia related to delayed catabolism of triglyceride-rich lipoprotein particles. Altered apolipoprotein C-III (apoC-III) metabolism may contribute to dyslipidemia in CKD. To further characterize the dyslipidemia of CKD, we investigated the kinetics of plasma apoC-III in 7 nonobese, nondiabetic, non-nephrotic CKD subjects and 7 age-and sex-matched healthy controls, using deuterated leucine ([5, 5, 5, 2 H 3 ]leucine), gas chromatography-mass spectrometry, and multicompartmental modeling. Compared with controls, CKD subjects had higher concentrations of plasma and VLDL triglycerides and plasma and VLDL apoC-III ( P < 0.05). The increased plasma apoC-III concentration was associated with a decreased apoC-III fractional catabolic rate (FCR) (1.21 ± 0.15 vs. 0.74 ± 0.12 pools/day, P = 0.03). There were no differences between apoC-III production rates of controls and those of CKD subjects. In CKD subjects, plasma apoC-III concentration was signifi cantly and negatively correlated with apoC-III FCR ( r = ؊ 0.749, P = 0.05) but not with apoC-III production rate. Plasma apoC-III concentration was positively correlated with plasma and VLDL triglycerides and VLDL apoB concentrations and negatively correlated with VLDL apoB FCR ( P < 0.05 for all). ApoC-III FCR was negatively correlated with plasma and VLDL triglycerides and VLDL apoB concentration and positively correlated with VLDL apoB FCR ( P < 0.05 for all). Altered plasma apoC-III metabolism is a feature of dyslipidemia in moderate CKD. Modifi cation of apoC-III catabolism may be an important therapeutic target for reducing cardiovascular disease risk in moderate

Multiplexed peptide analysis for kinetic measurements of major human apolipoproteins by LC/MS/MS

“…In addition, HDLApoA-II FCRs were close to those obtained for HDL-ApoA-I and ensuing PRs were also consistent with previous estimates ( 21,26 ). Similar fi ndings were observed for ApoE and ApoC-III ( 19,20,28 ), although the patients studied and the study design were not perfectly comparable. As previously explained ( 28 ) and unlike ApoE ( 19,20 ), ApoC-III FCRs calculated in VLDL and HDL were similar, supporting rapid exchanges of ApoC-III between both particles.…”

“…As shown by the Bland-Altman analysis, the enrichments measured by LC/MS/MS in this study were identical to those measured with the conventional GC/MS method and were in the same range as those reported previously by others using similar stable isotope protocols and the GC/MS method for ApoA-I ( 15,26 ) and ApoB100 ( 20,27 ). Similar results have been also reported for ApoA-II ( 21,26 ), ApoE ( 19,20 ), and ApoC-III ( 20,28 ). To the best of our knowledge, no data have been published for ApoC-II with GC/MS measurements.…”

“…Similar fi ndings were observed for ApoE and ApoC-III ( 19,20,28 ), although the patients studied and the study design were not perfectly comparable. As previously explained ( 28 ) and unlike ApoE ( 19,20 ), ApoC-III FCRs calculated in VLDL and HDL were similar, supporting rapid exchanges of ApoC-III between both particles. We found similar data for ApoC-II but, to our knowledge, no previous work can support this fi nding.…”

Relation of Serum Lipids and Lipoproteins with Progression of CKD

“…Despite this limitation, the stratified analyses by baseline statin use were consistent with overall results. This study did not evaluate novel measures of lipoproteins measured by nuclear magnetic resonance spectroscopy (such as plasma apoC-III) that have been associated in cross-sectional studies with kidney function (37). The current analysis also did not assess whether dyslipidemia contributes to the high risk of cardiovascular disease seen in CKD, but future reports from the CRIC study will do so.…”

Complexities of plasma apolipoprotein C-III metabolism

“…In the April issue of the Journal of Lipid Research , Ooi and colleagues ( 22 ) evaluated the metabolism of apoC-III in patients with chronic renal failure, a condition associated with a high incidence of cardiovascular disease. The principal fi nding was a low fractional catabolic rate (FCR) for apoC-III in VLDL of renal patients compared with controls.…”