Chronic kidney disease delays VLDL-apoB-100 particle catabolism: potential role of apolipoprotein C-III

Doris T Chan,Gursharan K Dogra,Ashley B Irish,Esther M Ooi,P Hugh Barrett,Dick C Chan,Gerald F Watts

doi:10.1194/jlr.p900003-jlr200

Abstract

To determine the relative contribution of obesity and/or insulin resistance (IR) in the development of dyslipidemia in chronic kidney disease (CKD), we investigated the transport of apolipoprotein (apo) B-100 in nonobese, nondiabetic, nonnephrotic CKD subjects and healthy controls (HC). We determined total VLDL, VLDL(1), VLDL(2), intermediate density lipoprotein (IDL), and LDL-apoB-100 using intravenous D3-leucine, GC-MS, and multicompartmental modeling. Plasma apoC-III and apoB-48 were immunoassayed. In this case control study, we report higher plasma triglyceride, IDL-, VLDL-, VLDL(1)-, and VLDL(2)-apoB-100 concentrations in CKD compared with HC (P < 0.05). This was associated with decreased fractional catabolic rates [FCRs (pools/day)] [IDL:CKD 3.4 (1.6) vs. HC 5.0 (3.2), P < 0.0001; VLDL:CKD 4.8 (5.2) vs. HC 7.8 (4.8), P = 0.038; VLDL(1):CKD 10.1 (8.5) vs. HC 29.5 (45.1), P = 0.007; VLDL(2):CKD 5.4 (4.6) vs. HC 10.4 (3.4), P = 0.001] with no difference in production rates. Plasma apoC-III and apoB-48 were significantly higher in CKD (P < 0.001) and both correlated with impaired FCRs of VLDL, VLDL(1), and VLDL(2) apoB-100 (P < 0.05). In CKD, apoC-III concentration was the only independent predictor of clearance defects in VLDL and its subfractions. Moderate CKD in the absence of central adiposity and IR is associated with mild hypertriglyceridemia due to delayed catabolism of triglyceride rich lipoproteins, IDL, and VLDL, without changes in production rate. Altered apoC-III metabolism may contribute to dyslipidemia in CKD, and this requires further investigation.

Highlights

Cardiovascular (CV) morbidity and mortality is increased in patients with mild renal dysfunction [1]
We have demonstrated that nonobese subjects with moderate chronic kidney disease (CKD) have mild hypertriglyceridemia that relates to higher plasma concentrations of total VLDL, VLDL1, VLDL2, and intermediate density lipoprotein (IDL) apoB-100
This could be a consequence of impaired clearance of IDL apoB-100, and of total VLDL apoB-100, including its major subclasses, with no significant difference in corresponding production rates

Summary

Introduction

Cardiovascular (CV) morbidity and mortality is increased in patients with mild renal dysfunction [1]. Dysregulation of lipoprotein metabolism can develop early in renal disease with alteration in apolipoprotein concentrations in spite of normal plasma lipid levels [2]. Raised plasma triglyceride concentration is recognized as an independent risk factor for cardiovascular disease (CVD) in nonrenal subjects [3] and may reflect the direct atherogenic potential of triglyceride-rich lipoproteins (TRLs), VLDLs and intermediate density lipoproteins (IDLs) [4]. VLDL and IDL apolipoprotein (apo) B-100 accumulation has been reported in kinetic turnover studies of dialysis patients [5,6,7] and in obese chronic kidney disease (CKD) patients not yet on dialysis [8]. Several kinetic studies have shown that IR increases FFA availability, which stimulates the release of large triglyceride-rich VLDL1 particles without a change in the small dense cholesterol-rich VLDL2 subfraction secretion [13, 14]

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