HDL metabolism in hypertriglyceridemic states: an overview

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Abstract

Reduced plasma high-density lipoprotein (HDL) cholesterol levels have been recognized as a highly significant independent risk factor for atherosclerotic cardiovascular disease. HDL levels are also inversely related to plasma triglyceride levels and there is a dynamic interaction between HDL and triglyceride (TG) rich lipoproteins in vivo. The mechanisms underlying the lowering of HDL in hypertriglyceridemic states have not been fully elucidated, but there is evidence to suggest that triglyceride enrichment of HDL, a common metabolic consequence of hypertriglyceridemia, may play an important role in this process. There is accumulating evidence to suggest that the primary mechanisms leading to reduced plasma HDL cholesterol levels and HDL particle number in hypertriglyceridemic states may be due to any one or a combination of the following possibilities: (1) small HDL particles, which are the product of the intravascular lipolysis of triglyceride-enriched HDL, may be cleared more rapidly from the circulation, (2) triglyceride-enriched HDL may be intrinsically more unstable in the circulation, with apo A-I loosely bound, (3) the lipolytic process itself of triglyceride-enriched HDL may lower HDL particle number by causing apo A-I to be shed from the HDL particles and cleared from the circulation, (4) a dysfunctional lipoprotein lipase or reduced LPL activity may contribute to the lowering of HDL levels by reducing the availability of surface constituents of triglyceride-rich lipoproteins that are necessary for the formation of nascent HDL particles. This review summarizes the evidence that triglyceride-enrichment of HDL is an important factor determining the rate at which HDL is catabolized, a mechanism which could explain, at least in part, the reduced plasma HDL cholesterol levels and particle number frequently observed in hypertriglyceridemic states.

Introduction

Reduced plasma HDL cholesterol levels have been recognized as a very potent independent risk factor for atherosclerotic cardiovascular disease (ACVD) [1], [2], [3], [4]. Accordingly, the study of the cardioprotective properties of HDL has become the topic of intense scientific scrutiny in recent years. However, mechanisms whereby HDL protects against the development of ACVD remain to be fully elucidated. One of several hypotheses that have been suggested over the years pertains to the significant role of HDL in a process referred to as reverse cholesterol transport [5], [6]. According to this concept, an increased plasma concentration of HDL promotes the net movement of cholesterol from extrahepatic tissues back to the liver, thereby reducing the ‘probability’ of accumulation of cholesterol in peripheral tissues, a process which may ultimately reduce atherosclerosis. As will be reviewed below, the metabolic fate of HDL-associated cholesterol through the reverse cholesterol transport pathway is intimately linked to the metabolism of triglyceride rich lipoproteins [5]. Indeed, one mechanism whereby the cholesteryl esters initially carried within the HDL particles are transported to the liver is through their transfer to apo B-containing lipoproteins by the cholesteryl ester transfer protein (CETP) [7], with the eventual uptake of these lipoproteins by hepatocytes [8]. HDL has also been shown to promote fibrinolysis [9], [10], to act as an anti-oxidant [11], [12] and to reduce LDL uptake by endothelial cells by competing for the LDL receptor [13]. Thus, the magnitude to which the reverse cholesterol transport pathway is involved in protecting against atherosclerosis remains to be clearly established, and it must be acknowledged that other anti-atherogenic properties of HDL may also play an important role in this process [6].

Plasma concentrations of HDL cholesterol and apolipoprotein A-I, the major protein moiety of HDL, are inversely correlated with plasma triglyceride concentrations [5], [14], [15], [16], [17]. As mentioned above, there is a dynamic interaction between triglyceride-rich lipoproteins and HDL particles [18], and a number of mechanisms underlying the inverse association between plasma triglyceride and HDL concentrations have been proposed. First, hypertriglyceridemia may arise, among other factors, from the dysfunctional intravascular lipolysis of triglyceride-rich lipoproteins [19], [20]. Because a significant proportion of the surface constituents of HDL is derived from the hydrolysis of fasting and postprandial triglyceride-rich lipoproteins [21], [22], reduced lipolysis of these particles may have a significant impact on the formation of nascent HDL particles by reducing the availability of the surface constituents necessary for their formation. Second, hypertriglyceridemia from a variety of causes results in an increased mass transfer of triglyceride from triglyceride-rich lipoproteins to HDL through the action of CETP, with concomitant heteroexchange of cholesteryl esters, a process which reduces the cholesterol content of each HDL particle [23]. Finally, the same process frequently leads to triglyceride enrichment of HDL, particularly in hypertriglyceridemic individuals [24], [25], [26], and studies have shown a significant inverse correlation between postprandial HDL triglyceride enrichment and fasting HDL cholesterol levels in humans [27], [28]. There is accumulating evidence to suggest that triglyceride enrichment of HDL may have a significant impact on the metabolism of HDL particles, by predisposing HDL to more rapid clearance from the circulation, thus explaining part of the inverse relationship between plasma triglyceride and HDL levels. Evidence supporting this hypothesis will be summarized in the present review, with emphasis on some of the factors intrinsic (i.e. HDL composition and size) and extrinsic (i.e. enzymes involved in HDL metabolism) to HDL that may be implicated in this process.

Section snippets

Indirect evidence that tryglyceride levels affect HDL metabolism

Most HDL apolipoproteins, unlike apolipoprotein (apo) B in VLDL and LDL subfractions, are subjected to non-specific exchange between plasma lipoproteins, particularly between HDL subspecies [29], [30], [31]. In addition, the lipid and protein components of HDL may follow relatively distinct metabolic pathways, which are independently regulated. For these reasons, it has been difficult to trace the production and the catabolism of ‘whole’ HDL particles in vivo. In general, human and animal

Effects of particle size

In their study, Brinton et al. [34] did not directly measure HDL particle size but used a surrogate of particle diameter, i.e. the HDL cholesterol/A-I+A-II molar ratio. Earlier studies in humans have shown no difference in the clearance of HDL2 (large particles) and HDL3 (small particle) [43], but in those studies the problem of tracer exchange between particles in the circulation may have obscured real differences in clearance. Saku et al. [44] demonstrated that pooled human LpAI (HDL

Importance of intravascular remodeling of HDL

There is accumulating evidence to suggest that lipolysis of HDL triglycerides and phospholipids intravascularly, a process leading to the formation of small lipolytically modified HDL particles [58], may be an important factor to consider when investigating the determinants of HDL metabolism. This process may become particularly significant as the triglyceride content of HDL increases [59], [60] and may account for a significant proportion of the inverse relationship between HDL particle size

Conclusions

It is unlikely that reduced plasma HDL levels in hypertriglyceridemic states can be ascribed to only one ‘disruption’ among the various metabolic pathways regulating HDL levels. Instead, the mechanisms of HDL lowering will likely prove to be multi-factorial. As reviewed above and as shown in Fig. 2, the primary mechanisms leading to reduced plasma HDL levels in hypertriglyceridemic states can be due to any one or a combination of possibilities which have all been supported by sound data during

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