Analysis of the relationship between triglyceridemia and HDL-phospholipid concentrations: consequences on the efflux capacity of serum in the Fu5AH system

Abstract

The high triglyceride/low HDL-cholesterol trait is a common finding in the general population. The aim of the present study was to analyze and interpret the relationships between triglycerides (TG), HDL-related parameters and serum cholesterol efflux potential in an asymptomatic population including both normo- and hyperlipidemic individuals. In a large sample (n=1143) of this population, there was a negative correlation between TG and HDL-cholesterol (HDL-C) (r=−0.49, P<0.0001) whereas the negative correlation between TG and HDL-phospholipid (HDL-PL) (r=−0.29, P<0.0001) was weaker, leading to a strong positive correlation between TG and HDL-PL/C ratio (r=0.58, P<0.0001). Thus, increased TG concentrations were associated with an enrichment of HDL with PL. Since we have demonstrated previously that HDL-PL is the major determinant for cholesterol efflux potential from Fu5AH rat hepatoma cells, we determined the effect of the variations in HDL lipid composition on the cholesterol efflux capacity in a subsample of 198 subjects. Compared with normolipidemic subjects (NLP) (TG≤1.7 mmol/l; LDL-C≤4.1 mmol/l, n=58), hypertriglyceridemic subjects (HTG) (TG>1.7 mmol/l, n=63) exhibited lower HDL-C levels (1.08±0.21 vs. 1.25±0.32, P=0.0003) whereas they showed similar HDL-PL concentrations (1.25±0.21 vs. 1.25±2.7) and, thus, higher HDL-PL/C ratio (1.17±0.15 vs. 1.02±0.14, P=0.0001). The relative efflux capacity of serum measured in the Fu5AH system (5% serum, 4 h incubation at 37°C) was on average identical in the HTG and NLP groups. Thus, this study provides evidence that despite decreased HDL concentrations, as determined routinely by the HDL-C assay, some HTG subjects maintained serum cholesterol efflux capacity thanks to the enrichment of HDL with PL.

Introduction

Epidemiological relationships have been established between hypertriglyceridemia and coronary artery diseases [1], [2], [3], [4], [5], [6], [7] but the causal role of triglycerides as a cardiovascular risk factor is still being investigated in a number of current studies. Hypertriglyceridemia is first implicated in the genesis of atherosclerosis through the deleterious effects of triglyceride-rich lipoproteins (TGRL) on the arterial wall leading to a dysregulation of the endothelial function and to lipid deposition [8]. Second, there is a well-documented negative relationship between serum triglyceride and HDL-cholesterol concentrations [9], [10], which suggests that the atherogenicity of hypertriglyceridemia also depends on the low level of the HDL particles. Indeed, a number of identified metabolic properties of HDL have determined their protective role against atherosclerosis development [11] and most of the results from epidemiological studies give support to an inverse association between HDL concentrations and coronary artery diseases [12].

It is now established that metabolic interactions between HDL and TGRL must explain the common high triglyceride/low HDL-cholesterol trait. First, a dysfunctional lipoprotein lipase (LPL) or reduced LPL activity may contribute to the lowering of HDL levels by reducing the availability of surface constituents of TGRL that are necessary for the formation of nascent HDL particles [13], [14]. Second, during the transitory stage of TGRL in plasma, a reciprocal exchange of cholesteryl esters from HDL towards TGRL and of triglycerides from TGRL towards HDL occurs through the activity of the cholesteryl ester transfer protein (CETP), leading, thus, to a triglyceride enrichment of HDL. Third, there is accumulating evidence that triglyceride enrichment of HDL may have a significant impact on the metabolism of HDL particles by enhancing its clearance through the hepatic lipase (HL), which facilitates the catabolism of HDL [15], [16], [17], [18]. Thus, it is described classically that hypertriglyceridemia will reduce HDL-cholesterol concentrations, as a result of delayed lipolysis of TGRL, enhanced transfer of cholesteryl esters to TGRL and enhanced HDL catabolism by HL.

In addition to the mechanisms mentioned above, the relationship between triglycerides and HDL is influenced also by two other more recently described processes, regarding the phospholipid and apolipoprotein AI (apo AI) contents of HDL. First, an active transfer of phospholipids from TGRL towards HDL is mediated by the activity of a phospholipid transfer protein (PLTP) [19]. A direct relationship between triglycerides and endogenous PLTP activity has been demonstrated [20], which suggests that hypertriglyceridemia will accentuate the extent of phospholipid transfer from TGRL to HDL. The potential phospholipid enrichment of HDL, linked to hypertriglyceridemia, appears as a critical question since it is well documented that phospholipid is a major determinant for the ability of circulating HDL to remove and transport cholesterol released by a number of phospholipid-sensitive cells [21], [22], [23], [24], [25]. Second, it has been demonstrated that the remodeling of HDL mediated by CETP, HL and PLTP activities provokes the release of unassociated apolipoprotein AI from HDL, which may be either rapidly catabolyzed or involved in the removal of cellular cholesterol as a fast early cholesterol acceptor [26], [27], [28]. These two latter processes are modulating the concept of a deleterious association between elevated triglycerides and low HDL-cholesterol and suggested that this association should be re-considered, taking into account the HDL-phospholipid and the apo AI parameters.

The aim of the present study was to analyze and interpret the relationships between serum triglyceride and HDL parameters (HDL-cholesterol, HDL-phospholipid and apo AI) in a population of asymptomatic subjects including both normo- and hyperlipidemic individuals. Since we demonstrated clearly that hypertriglyceridemia was associated with a HDL phospholipid enrichment, we further investigated the cellular cholesterol efflux capacity of serum in the Fu5AH system, known as the most sensitive cells to HDL-phospholipid [21], [22], [23], [24], [25].