Determinants of VLDL composition and apo B-containing particles in familial combined hyperlipidemia

Highlights

• Two different mechanisms for the dyslipidemia severity in FCHL cases are proposed.

• Apo CIII, Apo AII, and adiponectin are novel determinants of VLDL-TG content as surrogate of VLDL composition.

• Higher VLDL-TG levels were found in cases within the highest tertile of Apo CIII.

• Subjects with mixed hyperlipidemia phenotype have the highest Apo CIII levels.

Abstract

Background

In familial combined hyperlipidemia (FCHL) the severity of the dyslipidemia is determined by an overproduction of VLDL (very low density lipoprotein) particles and by its abnormal lipid composition. However, few are known regarding the metabolic factors that determine these abnormalities. We investigated the impact of metabolic factors on the number of atherogenic particles (apolipoprotein B level (apoB)) and the triglyceride content of very low-density lipoproteins (VLDLs-TG).

Methods

A cross-sectional study done in FCHL subjects and gender and age-matched healthy subjects.

A clinical assessment, lipid profile and plasma concentrations of insulin, apolipoprotein CIII (apo CIII), apolipoprotein AII (apo AII), high sensitive C-reactive protein (HS-CRP), adiponectin and leptin were documented in 147 FCHL patients and 147 age-matched healthy subjects. Multivariate regression models were performed to investigate the independent determinants of VLDL-TG and apo B levels adjusting for confounding factors.

Results

The variables that determined the VLDL-triglyceride content as a surrogate of VLDL composition were apo CIII (β = 0.365, p < 0.001), insulin (β = 0.281, p < 0.001), Apo AII (β = 0.145, p < 0.035), and adiponectin levels (β = − 0.255, p < 0.001). This model explained 34% of VLDL composition (VLDL-TG) variability. However, none of these variables were independent contributors of apo B-containing particles.

Conclusions

In patients with FCHL apo CIII, apo AII and adiponectin are major novel factors determining the VLDL particle composition. However, such factors do not explain apo B-containing particles.

Introduction

Familial combined hyperlipidemia (FCHL) is a highly prevalent, complex disorder associated with increased cardiovascular mortality [1], [2], [3]. It is the most frequent primary dyslipidemia in Mexico [4]. The disease is characterized by elevated apolipoprotein B levels (apo B) (above the 90th percentile for the specific ethnic group) in combination with isolated hypertriglyceridemia, isolated hypercholesterolemia or mixed hyperlipidemia [5]. The FCHL phenotype shows remarkable variability. However, the factors which determine the phenotypic expression of the disease are only partially known [6], [7]. The high levels of apolipoprotein B and a predominance of small dense low-density lipoprotein (LDL) particles are markers of atherosclerotic burden [8]. In subjects with FCHL, the development of atherosclerosis is thought to be associated with an overproduction of liver-derived apolipoprotein B (in very low-density lipoproteins (VLDLs)), an abnormal VLDL particle composition, and a reduction in lipoprotein lipase (LPL) activity. The severity of the dyslipidemia associated with FCHL can be evaluated by measuring some of these features.

Variables that may regulate the phenotypic expression of FCHL include hyperinsulinemia, the plasma concentration of several apolipoproteins, genetic factors, and inflammatory mediators [9], [10].

Hyperinsulinemia is a well-known factor to regulate apo B containing lipoprotein synthesis and catabolism. However, its role as a determinant of the severity of the dyslipidemia is controversial, as only around 50% of FCHL subjects have hyperinsulinemia [11], [12]. Changes in the concentrations of the apolipoproteins AII (apo AII) and CIII (apo CIII) have also been implicated in the pathogenesis of FCHL based on animal models and clinical observations. In animal models, the overexpression of apo AII results in the overproduction of VLDL, insulin resistance and low levels of HDL-C (high density lipoprotein cholesterol) [13], [14], [15]. Apo CIII inhibits LPL activity and regulates lipid and lipoprotein synthesis in the liver [16], [17], [18], [19], [20], [21]. Adipose tissue secretes several adipocytokines (i.e. adiponectin [22], [23], [24], leptin [25], [26], and others) that regulate appetite, immunity, inflammation, and glucose/lipid metabolism. The influence of the majority of these factors on the severity of the FCHL dyslipidemia is unknown.