The concurrence of visceral obesity, insulin resistance and dyslipidaemia comprises the concept of the metabolic syndrome. The metabolic syndrome is an escalating problem in developed and developing societies that tracks with the obesity epidemic. Dyslipidaemia in the metabolic syndrome is potently atherogenic and, hence, is a major risk factor for CVD (cardiovascular disease) in these subjects. It is globally characterized by hypertriglyceridaemia, near normal LDL (low-density lipoprotein)-cholesterol and low plasma HDL (high-density lipoprotein)-cholesterol. ApoC-III (apolipoprotein C-III), an important regulator of lipoprotein metabolism, is strongly associated with hypertriglyceridaemia and the progression of CVD. ApoC-III impairs the lipolysis of TRLs [triacylglycerol (triglyceride)-rich lipoproteins] by inhibiting lipoprotein lipase and the hepatic uptake of TRLs by remnant receptors. In the circulation, apoC-III is associated with TRLs and HDL, and freely exchanges among these lipoprotein particle systems. However, to fully understand the complex physiology and pathophysiology requires the application of tracer methodology and mathematical modelling. In addition, experimental evidence shows that apoC-III may also have a direct role in atherosclerosis. In the metabolic syndrome, increased apoC-III concentration, resulting from hepatic overproduction of VLDL (very-LDL) apoC-III, is strongly associated with delayed catabolism of triacylglycerols and TRLs. Several therapies pertinent to the metabolic syndrome, such as PPAR (peroxisome-proliferator-activated receptor) agonists and statins, can regulate apoC-III transport in the metabolic syndrome. Regulating apoC-III metabolism may be an important new therapeutic approach to managing dyslipidaemia and CVD risk in the metabolic syndrome.

INTRODUCTION

Compelling evidence from a large number of clinical studies has established that elevated triacylglycerols (triglycerides) are an independent risk factor for atherosclerotic CVD (cardiovascular disease) [15]. The finding of TRLs (triacylglycerol-rich lipoproteins) and TRL remnants in atheromous plaques provides critical evidence supporting their direct role in atherogenesis. In the metabolic syndrome, hypertriglyceridaemia commonly co-exists with other CVD risks that include central obesity, impaired insulin and glucose metabolism, low HDL (high-density lipoprotein)-cholesterol levels and hypertension [6]. Hypertriglyceridaemia is associated with an overproduction of VLDL (very-low-density lipoprotein) particles, a collective consequence of insulin resistance and increased lipid substrate availability in the liver and delayed catabolism of TRLs, TRL remnants and apo (apolipoprotein) B-containing lipoproteins [79]. The delayed catabolism of TRLs and its remnants is a consequence of depressed activities of LPL (lipoprotein lipase) and hepatic remnant receptors, increased apoC-III concentrations, and competition of dietary and hepatic-derived lipoproteins for common removal pathways [1013].

In the present review, we will discuss the present and developing knowledge of the role of apoC-III in lipoprotein metabolism and CVD, as well as treatments for regulating apoC-III metabolism in high-risk individuals with dyslipidaemia, particularly those with the metabolic syndrome.

APOC-III: MOLECULAR BIOCHEMISTRY AND PHYSIOLOGY

ApoC-III is synthesized in the liver and, to a lesser extent, by the intestines as a small 99-amino-acid peptide [14,15]. Following removal of the 20-amino-acid signal peptide in the endoplasmic reticulum, a mature apoC-III protein of 79 amino acids with a molecular mass of 8.8 kDa is formed. It is present as a non-glycosylated isoform (apoC-III0) or as a glycosylated isoform with either one or two moles of sialic acid (apoC-III1 and apoC-III2 respectively) [16,17]. All three isoforms have the same half-life in plasma, suggesting similar synthesis and catabolic mechanisms, and possibly similar physiological functions.

ApoC-III is associated with apoB-containing lipoproteins and HDL, and exchanges rapidly between these particles (Figure 1). Various nomenclatures have been used to describe lipoproteins containing apoC-III. Alaupovic et al. [18] first defined the term LpB:C to describe the concentration of apoB-containing lipoproteins enriched with apoC-III. The development of methods to measure apoC-III concentrations, described later in this review, have led to additional terminologies. For example, apoC-III-LpB and apoC-III-non-LpB describes the concentration of apoC-III associated with apoB-containing lipoproteins and non-apoB-containing lipoproteins respectively [19]. This nomenclature has been used throughout this review.

Pictorial representation of the free exchange of apoC-III between apoB-containing lipoproteins and HDLs in the circulation

Figure 1
Pictorial representation of the free exchange of apoC-III between apoB-containing lipoproteins and HDLs in the circulation
Figure 1
Pictorial representation of the free exchange of apoC-III between apoB-containing lipoproteins and HDLs in the circulation

During the hydrolysis of VLDL triacylglycerols by LPL, apoC-III redistributes from VLDL to HDL, and is subsequently transferred back to newly synthesized TRL particles [20,21]. In vitro and in vivo radiotracer studies have demonstrated rapid exchange and equilibration between TRLs and HDL particles [2224]; however, other radiotracer studies have suggested non-equilibrating pools of apoC-III that do not exchange between VLDL and HDL [25,26]. Recent endogenous stable isotope tracer studies suggest that the kinetics of apoC-III in VLDL and HDL are similar, supporting the concept of a kinetically homogeneous plasma apoC-III pool [27]. Methodological differences may explain the discrepancies among these findings. In subjects with normolipidaemia, the majority of plasma apoC-III is bound to HDL [23]. By contrast, in subjects with hypertriglycerideamia, the majority is bound to TRLs [22]. The mechanism regulating the putative apoC-III exchange between TRLs and HDL, however, remains unknown.

The apoC-III gene is located on human chromosome 11 between the apoA-I and apoA-IV genes (Figure 2) [28]. The exact evolutionary biology of apoC-III is unknown. We know that apoCs are involved in regulating fat transport in plasma and, hence, in maintaining energy flux in vivo; apoC-IIII could mediate some of the effects of insulin on triacylglycerol clearance in the fasting state, and we speculate that its increase in acute inflammation may confer protection against infective organisms by increasing the plasma lipid pool that counteracts lipopolysaccharide. ApoC-III shares a common apoA-I-like ancestral gene with other apoCs, apoAs and apoEs [29].

Schematic representation of the apoC-III gene

Figure 2
Schematic representation of the apoC-III gene

PPARα agonists inhibit the expression of apoC-III, whereas inflammatory signalling (e.g. NF-κB) induce the expression of apoC-III. Polymorphisms in exons 3 and 4 have been associated with increased apoC-III and triacylglycerol concentrations. Adapted from Figure 4-40 in [28], with permission.

Figure 2
Schematic representation of the apoC-III gene

PPARα agonists inhibit the expression of apoC-III, whereas inflammatory signalling (e.g. NF-κB) induce the expression of apoC-III. Polymorphisms in exons 3 and 4 have been associated with increased apoC-III and triacylglycerol concentrations. Adapted from Figure 4-40 in [28], with permission.

Several pathways have been proposed for the regulation of apoC-III gene expression. ApoC-III expression is regulated, in part, by insulin via the promoter IRE (insulin-response element) on the apoC-III gene [30]. Transcription of the apoC-III gene is down-regulated by insulin [31]. The transcription of the apoC-III gene is also mediated by PPARs (peroxisome-proliferator-activated receptors) [32]. The induction of PPARs, principally the PPARα form, reduces apoC-III gene expression [33,34]. These experimental findings suggest that, in insulin-resistant states, such as the metabolic syndrome and Type 2 diabetes, the expression and secretion of apoC-III by the liver and intestines are likely to be dysregulated.

APOC-III: BIOCHEMICAL ANALYSES

Measuring plasma apoC-III concentrations in plasma

Sensitive, accurate and specific methods for routine measurements of apoC-III are available. The most widely used is an immunoturbidimetric assay available from Wako Pure Chemicals Industries and Daiichi Chemicals. The principle of this assay is that, when a serum or plasma sample containing apoC-III is mixed with a buffer containing an anti-(human apoC-III) antibody, an insoluble turbid aggregate is formed. The degree of turbidity is measured optically and is proportional to the amount of apoC-III. ApoC-III can also be measured by ELISA [35] and by electroimmunodiffusion (Hydragel LP CIII; Sebia). Both fresh and frozen (−80 °C) sera or plasma samples can be used to measure total apoC-III concentrations. The reference values for total apoC-III concentrations have been quoted as 92.5±33.2 mg/l [36] and 112.2±31 mg/l [37].

Measuring apoC-III concentrations in non-apoB-containing subfractions

The Hydragel LP CIII kit allows for the quantification of total plasma apoC-III and apoC-III-non-LpB (after precipitation of apoB-containing lipoproteins) in human plasma by electroimmunodiffusion on mildly alkaline-buffered agarose gels [38]. These gels contain anti-(apoC-III) mono-specific antibodies. Following protein migration, the resulting rockets are stained with Acid Violet solution. The excess stain is removed with an acid/alcohol mixed solution, and the height of the resulting immunoprecipitation rockets is proportional to the apoC-III concentration. Total plasma apoC-III and apoC-III-non-LpB concentrations are then calculated from the standard curve, and apoC-III-LpB concentrations are calculated as total apoC-III−apoC-III-non-LpB.

Extraction of apoC-III from VLDL and HDL subfractions

The specific laboratory methodologies associated with the extraction of apoC-III from VLDL and HDL are described in detail elsewhere [27,39]. In brief, lipoprotein fractions are isolated by sequential ultracentrifugation, and apoC-III is isolated from other apoproteins present in VLDL and HDL using preparative IEF (isoelectric focusing). Intralipid®, an artificial triacylglycerol/phospholipid emulsion, can also be applied prior to IEF separation to isolate apoC-III [27]. The principle of this methodology is that Intralipid® preferentially and rapidly extracts apoC proteins, thus minimizing the interference of other apoproteins that migrate with or near apoC-III by IEF separation [27].

MECHANISTIC MODELS OF APOC-III METABOLISM

Several mechanistic models have been developed to better understand the metabolism of apoC-III [40]. The apoC-III model shown in Figure 3(A) includes the secretion of apoC-III into the VLDL and HDL fractions, the exchange of apoC-III between VLDL and HDL, and the removal of apoC-III from plasma via both VLDL and HDL. This general compartment model is most consistent with our present understanding of apoC-III metabolism. From a theoretical standpoint, there is a unique solution or set of model parameters that can be determined for this model. Although the compartment model fits the apoC-III tracer results, the model parameters cannot be estimated with any degree of precision because of the rapid exchange of apoC-III between the VLDL and HDL fractions. The model shown in Figure 3(B) is the simplest model that describes apoC-III kinetics in the VLDL and HDL fractions. This model describes apoC-III kinetics using a single homogeneous plasma compartment that fits the VLDL- and HDL-apoC-III tracer results separately and estimates FCR (fractional catabolic rate) with high precision. As described below, the application of this model has elucidated the regulation of apoC-III metabolism in the metabolic syndrome [40,41].

Compartmental models describing apoC-III tracer kinetics

Figure 3
Compartmental models describing apoC-III tracer kinetics

Compartments 1–4 represent the leucine subsystem (compartment 2 is the plasma pool), and compartment 5 represents the intrahepatic delay compartment. In model A, compartments 6 and 7 represent the VLDL- and HDL-apoC-III respectively. In model B, compartment 6 represents VLDL-, HDL- or plasma apoC-III.

Figure 3
Compartmental models describing apoC-III tracer kinetics

Compartments 1–4 represent the leucine subsystem (compartment 2 is the plasma pool), and compartment 5 represents the intrahepatic delay compartment. In model A, compartments 6 and 7 represent the VLDL- and HDL-apoC-III respectively. In model B, compartment 6 represents VLDL-, HDL- or plasma apoC-III.

APOC-III AND THE PATHOPHYSIOLOGY OF DYSLIPIDAEMIA IN THE METABOLIC SYNDROME

In the general population, plasma total and TRL apoC-III concentrations are positively correlated with plasma triacylglycerol concentrations. Accordingly, variation in the expression of apoC-III has been associated with varying severity of hypertriglyceridaemia.

The primary role of apoC-III is as a regulator of lipolysis through non-competitive inhibition of endothelial-bound LPL. This enzyme hydrolyses triacylglycerols in TRLs, releasing fatty acids into the plasma and transforming large triacylglycerol-rich particles into smaller triacylglycerol-depleted remnant lipoproteins [42,43] (Figure 4). Individuals lacking apoC-III have low TRL levels, coupled with highly efficient lipolysis of triacylglycerols [44]. Furthermore, mice in which the apoC-III gene is genetically deleted also have low plasma triacylglycerol levels and efficient TRL catabolism [45]. ApoC-III at high concentrations may also inhibit HL (hepatic lipase), a lipolytic enzyme with triacylglycerol lipase and phospholipase A1 activity that is synthesized in the liver [46] (Figure 4). The inhibitory effect of apoC-III on HL reduces further the lipolysis and uptake of TRL remnants by the liver [47].

ApoC-III regulates lipoprotein metabolism by multiple mechanisms

Figure 4
ApoC-III regulates lipoprotein metabolism by multiple mechanisms

ABCA1, ATP-binding cassette A1; CE, cholesterol ester; FC, free cholesterol; SR-B1, scavenger receptor B-1.

Figure 4
ApoC-III regulates lipoprotein metabolism by multiple mechanisms

ABCA1, ATP-binding cassette A1; CE, cholesterol ester; FC, free cholesterol; SR-B1, scavenger receptor B-1.

More recently, apoC-III has been shown to stimulate VLDL synthesis in cultured cells [48,49]. The underlying mechanisms associated with this effect of apoC-III is unclear, but may relate to the inhibition of proteosome-mediated degradation of apoB, resulting in increased apoB synthesis and secretion [49], and increased synthesis of VLDL triacylglycerols [48]. ApoC-III may therefore play a key role in regulating VLDL output by the liver.

Cellular studies report that apoC-III may interfere with TRL and remnant binding to hepatic lipoprotein receptors. ApoC-III can abolish apoB- and apoE-mediated binding of lipoproteins to LDLR [LDL (low-density lipoprotein) receptor], either by masking or altering the conformation of apoB and apoE [50,51] (Figure 4). The binding of chylomicrons and VLDL particles to the LSR (lipolysis-stimulated receptor) is also significantly inhibited by apoC-III [52].

For the mechanistic reasons referred to above, we consider that elevated plasma apoC-III concentrations, and specifically its accumulation in TRLs and their remnants, is causally related to hypertriglyceridaemia in the metabolic syndrome.

LCAT (lecithin cholesterol acyltransferase) and CETP (cholesteryl ester transfer protein) are involved in TRL and HDL metabolism. The regulatory effect of apoC-III on LCAT activity, an enzyme that catalyses the maturation of nascent to mature HDL, remains conflicting [53,54]. It is thought that apoC-III may regulate LCAT activity indirectly through apolipoproteins that activate LCAT, although further studies are required. Little has been published concerning the effects of apoC-III on CETP, a glycoprotein that facilitates the exchange of neutral lipids between TRL and HDL particles. A preliminary finding from a study using recombinant HDL particles suggests that apoC-III may stimulate CETP activity [55]. Further studies are required to determine the relationship between apoC-III with LCAT and CETP and its implications on TRL and HDL metabolism in the metabolic syndrome.

Kinetic studies using tracer methodology have provided valuable insights into the potential regulatory effects of apoC-III in the metabolic syndrome with hypertriglyceridaemia. Elevated rates of plasma and VLDL-apoC-III production explain the higher plasma and VLDL-apoC-III levels these subjects [40,41]. The increased production rate and concentration of VLDL-apoC-III were both significantly associated with elevated VLDL triacylglycerols [56,57], consistent with several studies showing that elevated apoC-III concentrations are associated with increased VLDL-apoB secretion and decreased VLDL-apoB catabolism [5860]. Elevated plasma apoC-III concentrations were also associated with increased plasma concentrations of remnant-like protein cholesterol and apoB-48, consistent with the contribution of apoC-III to postprandial hypertriglyceridaemia in subjects with the metabolic syndrome [61]. The delayed catabolism of remnant-like particles was also reported to be related to elevated apoC-III, again supporting the notion that apoC-III inhibits lipolysis and hepatic update of TRL remnants [61]. These findings collectively support the concept that apoC-III is a key determinant in the clearance of TRLs and its remnants in hypertriglyceridaemic states, including visceral obesity, insulin resistance and the metabolic syndrome.

APOC-III AND CVD: EVIDENCE FROM CLINICAL, EXPERIMENTAL AND GENETIC STUDIES

Clinical studies

Results from several studies have demonstrated the importance of apoC-III as a predictor of CVD outcomes (Table 1). Both CLAS (Cholesterol-Lowering Atherosclerosis Study) and MARS (Monitored Atherosclerosis Regression Study) demonstrated that plasma apoC-III predicted progression of angiographic coronary artery disease [62,63]. CLAS also reported that a decrease in apoC-III-non-LpB was a significant independent predictor for increased progression of coronary lesions. In MARS, apoC-III-LpB predicted the risk of progression, independent of LDL-cholesterol concentrations. The ECTIM (Etude Cas-Temoin de l'Infarctus du Myocarde) study reported that subjects post-myocardial infarction had increased apoC-III-LpB levels compared with healthy control subjects [19]. The CARE (Cholesterol and Recurrent Events) trial demonstrated that apoC-III-LpB was a stronger predictor of coronary heart disease events than plasma triacylglycerols [64] (Figure 5). In a substudy of the CARE trial, the concentration of LDL particles containing apoC-III was an independent risk factor for coronary events in patients with diabetes [65]. This indicates that the atherogenecity of apoB particles may be conditional on the presence of apoC-III. In three cross-sectional analyses, higher apoC-III concentrations were associated with increased severity of CVD in subjects with angiographically defined coronary artery disease [66], with the metabolic syndrome [67] and with Type 2 diabetes [68]. Collectively, with the exception of one study [69], elevated apoC-III, in particular apoC-III-LpB, was a significant predictor of coronary events and progression of CAD [19,6264,6668,70].

Table 1
Clinical studies showing direct associations between apoC-III levels and CAD

↑, increase; ↓, decrease; OR, odds ratio; RR, relative risk.

ReferenceAuthorSubjectsStudy designFindings
[62Blankenhorn et al. (1990) 162 men with CAD in the CLAS trial Randomized placebo-controlled angiographic trial ↑ apoC-III risk factor for angiographic progression of CAD in the placebo group 
    ↓ apoC-III-non-LpB/apoC-III-LpB is associated with the progression of CAD in the placebo group 
    ↓ in apoC-III-non-LpB is a significant independent predictor for ↑ progression of CAD in the drug group 
[70Chivot et al. (1990) 74 men with CAD and 78 control men Case-control study ↑ apoC-III and apoC-III-LpB in subjects with CAD 
    ↑ apoC-III-LpB predicted CAD independent of triacylglycerols 
[69Genest et al. (1991) 145 men with CAD and 135 control men Case-control study ↓ apoC-III in subjects with CAD 
    LpB:C-III not different between CAD and control groups 
[63Hodis et al. (1994) 220 subjects with CAD and moderate dyslipidaemia in MARS trial Randomized double-blind placebo- controlled angiographic trial ↑ apoC-III-LpB is an independent predictor of progression of CAD 
    apoC-III-LpB >5.10 mg/dl, RR for progression of CAD=5.10 (1.4–17.1) 
[66Koren et al. (1996) 100 normotensive non-obese and non-diabetic men who had undergone coronary angiography Cross-sectional study ↑ apoC-III-LpB, ↑ CAD severity 
    ↓ apoC-III-non-LpB/apoC-III-LpB ratio associated with CAD 
[19Luc et al. (1996) 360 post-myocardial infarction and 489 healthy subjects in the ECTIM study Case-control study ↑ apoC-III-LpB in CAD 
    ↓ apoC-III-non-LpB/apoC-III-LpB ratio associated with CAD 
    apoC-III-non-LpB/apoC-III-LpB ratio not an independent predictor of CAD in a stepwise regression with triacylglycerols and HDL-cholesterol 
[68Gervaise et al. (2000) 188 subjects with Type 2 diabetes Cross-sectional study ↑ apoC-III and apoC-III-LpB in subjects with Type 2 diabetes 
    ↑ apoC-III-LpB associated with CAD 
    apoC-III-LpB >17 mg/l, OR for macroangiopathy=2.73 (1.33–5.60) 
    apoC-III-LpB >17mg/l, OR for CAD=3.95 (1.73–9.04) 
[64Sacks et al. (2000) 788 men with myocardial infarction Prospective nested, case-control study ↑ apoC-III-LpB in CAD 
    ↑ apoC-III-LpB predicted CAD independent of triacylglycerols, HDL-cholesterol and LDL-cholesterol 
    apoC-III-LpB >10.2 mg/dl, RR for recurrent coronary events=2.25 (1.4–3.6) 
[67Onat et al. (2003) 875 subjects with metabolic syndrome Cross-sectional study ↑ apoC-III-LpB associated with CAD 
    apoC-III-LpB >7.6 mg/dl, OR for CAD in women=3.22 (1.29–8.01) 
    apoC-III-LpB ≥8.0 mg/dl, OR for CAD in men=8.87 (2.64–29.8) 
    ↑ apoC-III and apoC-III-LpB associated with the metabolic syndrome 
    apoC-III-LpB >7.0 mg/dl, OR for metabolic syndrome=4.66 (3.43–6.32) 
ReferenceAuthorSubjectsStudy designFindings
[62Blankenhorn et al. (1990) 162 men with CAD in the CLAS trial Randomized placebo-controlled angiographic trial ↑ apoC-III risk factor for angiographic progression of CAD in the placebo group 
    ↓ apoC-III-non-LpB/apoC-III-LpB is associated with the progression of CAD in the placebo group 
    ↓ in apoC-III-non-LpB is a significant independent predictor for ↑ progression of CAD in the drug group 
[70Chivot et al. (1990) 74 men with CAD and 78 control men Case-control study ↑ apoC-III and apoC-III-LpB in subjects with CAD 
    ↑ apoC-III-LpB predicted CAD independent of triacylglycerols 
[69Genest et al. (1991) 145 men with CAD and 135 control men Case-control study ↓ apoC-III in subjects with CAD 
    LpB:C-III not different between CAD and control groups 
[63Hodis et al. (1994) 220 subjects with CAD and moderate dyslipidaemia in MARS trial Randomized double-blind placebo- controlled angiographic trial ↑ apoC-III-LpB is an independent predictor of progression of CAD 
    apoC-III-LpB >5.10 mg/dl, RR for progression of CAD=5.10 (1.4–17.1) 
[66Koren et al. (1996) 100 normotensive non-obese and non-diabetic men who had undergone coronary angiography Cross-sectional study ↑ apoC-III-LpB, ↑ CAD severity 
    ↓ apoC-III-non-LpB/apoC-III-LpB ratio associated with CAD 
[19Luc et al. (1996) 360 post-myocardial infarction and 489 healthy subjects in the ECTIM study Case-control study ↑ apoC-III-LpB in CAD 
    ↓ apoC-III-non-LpB/apoC-III-LpB ratio associated with CAD 
    apoC-III-non-LpB/apoC-III-LpB ratio not an independent predictor of CAD in a stepwise regression with triacylglycerols and HDL-cholesterol 
[68Gervaise et al. (2000) 188 subjects with Type 2 diabetes Cross-sectional study ↑ apoC-III and apoC-III-LpB in subjects with Type 2 diabetes 
    ↑ apoC-III-LpB associated with CAD 
    apoC-III-LpB >17 mg/l, OR for macroangiopathy=2.73 (1.33–5.60) 
    apoC-III-LpB >17mg/l, OR for CAD=3.95 (1.73–9.04) 
[64Sacks et al. (2000) 788 men with myocardial infarction Prospective nested, case-control study ↑ apoC-III-LpB in CAD 
    ↑ apoC-III-LpB predicted CAD independent of triacylglycerols, HDL-cholesterol and LDL-cholesterol 
    apoC-III-LpB >10.2 mg/dl, RR for recurrent coronary events=2.25 (1.4–3.6) 
[67Onat et al. (2003) 875 subjects with metabolic syndrome Cross-sectional study ↑ apoC-III-LpB associated with CAD 
    apoC-III-LpB >7.6 mg/dl, OR for CAD in women=3.22 (1.29–8.01) 
    apoC-III-LpB ≥8.0 mg/dl, OR for CAD in men=8.87 (2.64–29.8) 
    ↑ apoC-III and apoC-III-LpB associated with the metabolic syndrome 
    apoC-III-LpB >7.0 mg/dl, OR for metabolic syndrome=4.66 (3.43–6.32) 

Plasma apoC-III concentrations in VLDL+LDL and the risk of recurrent coronary events in the CARE study

Figure 5
Plasma apoC-III concentrations in VLDL+LDL and the risk of recurrent coronary events in the CARE study

Q, Quintiles. This Figure was drawn with data taken from [64], with permission.

Figure 5
Plasma apoC-III concentrations in VLDL+LDL and the risk of recurrent coronary events in the CARE study

Q, Quintiles. This Figure was drawn with data taken from [64], with permission.

Experimental and transgenic animal studies

The potential effects of apoC-III in atherogenesis have been examined in experimental studies. These suggest that apoC-III activates PKC (protein kinase C) and NF-κB (nuclear factor κB) expression of endothelial VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intracellular adhesion molecule-1), and the recruitment of monocytes to the vascular wall [7173] (Figure 6). Hence the apoC-III pathway may promote a diverse inflammatory response through monocyte–endothelial interactions and play a specific role in the development of atherogenesis.

ApoC-III induces β-integrin on monocyte, and VCAM-1 and ICAM-1 on endothelial cells

Figure 6
ApoC-III induces β-integrin on monocyte, and VCAM-1 and ICAM-1 on endothelial cells

This Figure was reproduced with permission from Professor Frank M. Sacks.

Figure 6
ApoC-III induces β-integrin on monocyte, and VCAM-1 and ICAM-1 on endothelial cells

This Figure was reproduced with permission from Professor Frank M. Sacks.

A large body of evidence supporting the role of apoC-III in atherogenesis has come from transgenic and gene-targeted mouse studies. Overexpression of human apoC-III in wild-type mice enhances the development of atherosclerosis [74], in association with elevated triacylglycerol and low HDL-cholesterol and apoA-I levels. Elevated apoC-III concentrations and gene expression were also associated with an increase in hepatic VLDL triacylglycerol production rate, decreased VLDL and remnant catabolic rates [75,76], and reduced TRL binding to proteoglycan matrix on the surface of endothelial cells where LPL is located. Overexpression of apoC-III in apoE-knockout mice resulted in the accumulation of TRLs and hypertriglyceridaemia [77], whereas overexpression of apoC-III in LDLR-knockout mice was associated with severe hypercholesterolaemia and atherosclerosis [78]. By contrast, targeted disruption of the apoC-III gene in mice results in rapid catabolism of TRLs, consistent with decreased inhibition of LPL and increased lipolysis [79], and protection from both fasting and postprandial hypertriglyceridaemia [45], implying protection against atherogenesis.

ApoC-III deficiencies and genetic polymorphisms

The consequence of a complete lack of apoC-III in human subjects on the changes in plasma lipoprotein levels and CVD is unclear. In most studies, apoC-III deficiency was coupled with an apoA-I deficiency; however, one genetic variant of apoC-III (Lys58→Glu) was associated with lower plasma apoC-III and triacylglycerol levels, and higher HDL-cholesterol and apoA-I concentrations [80]. Animal knockout studies provide some insight into the significance of apoC-III deficiency. ApoC-III-knockout mice had normal intestinal lipid absorption and hepatic VLDL triacylglycerols secretion, but a rapid clearance of VLDL triacylglycerols and VLDL cholesteryl esters from plasma that may explain the observed hypolipidaemia [81,82]. The enhanced LPL-mediated lipolysis of VLDL triacylglycerols in apoC-III-knockout mice was also shown to be independent of apoE [82]. Furthermore, experimental apoC-III deficiency may prevent hyperlipidaemia associated with the overexpression of apoE [81]. These studies support the concept that apoC-III is an effective inhibitor of VLDL triacylglycerols hydrolysis and a potential target for reducing CVD progression.

Polymorphisms in the apoC-III gene may have implications for hypertriglyceridaemia and susceptibility to CVD. Carriers of the C3238G gene variant have higher plasma apoC-III and triacylglycerol concentrations [8385]. However, whether this gene variant confers increased CVD risk is conflicting [86]. Homozygotes for the T−455C variant are resistant to insulin-mediated down-regulation of apoC-III gene transcription and have elevated triacylglycerol levels and increased CVD risk [87]. The C1100T variant is associated with increased triacylglycerol levels, predominantly in homozygotes [88]; however, this genetic variant was not associated with variations in apoC-III levels.

THERAPEUTIC REGULATION OF APOC-III

Statins

A rate-limiting step in cholesterol biosynthesis is the conversion of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) into mevalonic acid by HMG-CoA reductase [89]. Statins competitively inhibit this enzyme, decreasing the intracellular pool of cholesterol and reciprocally up-regulating LDLR activity. Independent of its effects on LDL and LDLR activity, statins lower the plasma concentration and cellular mRNA levels of apoC-III [64,9092] (Table 2). Although the precise mechanism for the effects of statins on apoC-III is not fully understood, it may relate to the activation of hepatic PPARα protein [93] and, hence, a reduction in the expression and secretion of apoC-III. Furthermore, statins improve insulin action in subjects with hypertriglyceridaemia [94]. This may translate to an insulin-dependent down-regulation of apoC-III gene transcription via the IRE in the apoC-III promoter.

Table 2
Mean percentage changes in total plasma apoC-III and lipid and lipoprotein concentrations in subjects with dyslipidaemia following lipid-regulating interventions

↑, increase; ↓, decrease. *Combination therapy with colestipol.

InterventionReferenceApoC-IIITriacylglycerolsLDL-cholesterolHDL-cholesterol
Statins [64,9092↓ 27% ↓ 7–30% ↓ 18–55% ↑ 5–15% 
Fibrates [33,97↓ 36% ↓ 20–50% ↓ 5–20% ↑ 10–20% 
Thiazolidinediones [100↓ 20% ↓ 16–30% ↑ 0–8% ↑ 14–15% 
Ezetimibe [112↓ 21% ↓ 6–11% ↓ 12–14% ↑ 1–5% 
Niacin [119↓ 31%* ↓ 20–50% ↓ 5–25% ↑ 15–35% 
Fish oil [113,114↓0-5% ↓ 25–44% ↓ 5–25% ↑ 0–8% 
Weight loss [123↓ 9% ↓ 5–15% ↓ 5–18% ↑ 0–9% 
InterventionReferenceApoC-IIITriacylglycerolsLDL-cholesterolHDL-cholesterol
Statins [64,9092↓ 27% ↓ 7–30% ↓ 18–55% ↑ 5–15% 
Fibrates [33,97↓ 36% ↓ 20–50% ↓ 5–20% ↑ 10–20% 
Thiazolidinediones [100↓ 20% ↓ 16–30% ↑ 0–8% ↑ 14–15% 
Ezetimibe [112↓ 21% ↓ 6–11% ↓ 12–14% ↑ 1–5% 
Niacin [119↓ 31%* ↓ 20–50% ↓ 5–25% ↑ 15–35% 
Fish oil [113,114↓0-5% ↓ 25–44% ↓ 5–25% ↑ 0–8% 
Weight loss [123↓ 9% ↓ 5–15% ↓ 5–18% ↑ 0–9% 

PPAR agonists

PPARs are nuclear transcription factors that regulate the expression of genes involved in lipid and lipoprotein metabolism. There are three PPAR isoforms (PPARα, PPARγ and PPARδ), each representing an intracellular ligand-induced receptor known to heterodimerize with RXR (retinoid X receptor) for transcriptional promotion of various enzymes [95].

PPARα agonists, also known as fibrates, regulate lipid metabolism and may diminish CVD events [96]. Reduction in the expression and levels of apoC-III is the most consistent effect of PPARα agonists [33]. A 36% reduction in plasma apoC-III levels was reported with fenofibrate treatment in the metabolic syndrome [97] (Table 2). Fibrates also increase acyl CoA synthase and fatty acid transporter protein; this facilitates intracellular transport, acylation and β-oxidation of fatty acids, with the net effect of decreasing fatty acid availability for triacylglycerol synthesis and VLDL-apoB secretion [98]. In vitro, fibrates can induce the expression of genes encoding LPL, apoA-I, apoA-II and ABCA1 (ATP-binding cassette A1).

PPARγ agonists, such as pioglitazone and rosiglitazone, improve insulin sensitivity in muscle, liver and fat, and are efficacious therapies in treating diabetic dyslipidaemia [99]. Pioglitazone was shown to significantly decrease apoC-III concentrations by reducing its production rate [100]. The mechanism whereby pioglitazone reduces the synthesis of apoC-III remains undetermined, but may involve the stimulation of PPARα [101] and improved insulin sensitivity leading to the down-regulation of apoC-III gene expression [102,103].

The role of PPARδ agonists on apoC-III concentrations and expression is not well known. Further studies are required to establish their effects on apoC-III metabolism and their role in the management of dyslipidaemia and CVD.

FXR (farnesoid X receptor) agonists

FXR is a member of the nuclear receptor superfamily that is expressed in the liver, intestines and kidneys [104]. Following heterodimerization with RXR, FXR binds and activates the transcription of genes via positive FXR-response elements [105]. FXR may also regulate lipid and lipoprotein metabolism [106]. Previous studies have reported that FXR agonists decrease plasma triacylglycerol and apoC-III concentrations [107,108]. The mechanism is unclear, but may relate to the down-regulation of apoC-III mRNA and protein expression [107], as suggested for PPARα in Figure 2.

Ezetimibe

Ezetimibe inhibits dietary and biliary cholesterol absorption at the brush border of the intestine by binding to the NCP1L1 (Niemann–Pick C1-like 1) transporter [109]. It has been shown to reduce LDL-cholesterol by 12–14%. [110]. The LDL-cholesterol-lowering effect of ezetimibe is predominantly associated with increases in catabolism of VLDL, IDL (intermediate-density lipoprotein) and LDL-apoB [111]. A recent trial demonstrated further that ezetimibe significantly reduced apoC-III and triacylglycerol concentrations in dyslipidaemic subjects [112] (Table 2); however, the effect of ezetimibe on apoC-III metabolism has not been elucidated and warrants further study.

Fish oils

n−3 Polyunsaturated fatty acids contained in fish oils may exert triacylglycerol- and apoC-III-lowering effects [113,114] (Table 2). The effects may be attributed to EPA (eicosapentaenoic acid), rather than DHA (docosahexaenoic acid). EPA regulates hepatic fatty acid oxidation and has a direct effect on TRL synthesis, assembly and secretion [115,116]. The mechanism underlying the apoC-III-lowering effect of fish oils is unclear, but may relate to the activation of PPARα [117] (Figure 2). Future studies are required to clarify the regulatory effects of fish oil on apoC-III metabolism and their role in managing dyslipidaemia in the metabolic syndrome.

Niacin

Nicotinic acid (or niacin) confers beneficial effects on all major plasma lipid and lipoprotein fractions, particularly by increasing HDL-cholesterol concentrations and decreasing both LDL-cholesterol and triacylglycerol concentrations [118]. In addition, niacin has been shown to reduce VLDL-apoC-III concentrations in subjects with hyperlipidaemia [119]. Niacin activates the G-protein-coupled nicotinic acid receptor [120] and inhibits diacylglycerol acyltransferase 2, the key enzyme in triacylglycerols synthesis [121] and hormone-sensitive triacylglycerol lipase, a lipolytic enzyme [122]. It is through the combination of these actions that niacin exerts a potent effect upon lipid and lipoprotein metabolism; however, the exact regulatory effect of niacin on apoC-III metabolism is unclear and warrants further study.

Lifestyle modifications

Weight loss has been associated with a reduction in plasma apoC-III concentrations in postmenopausal women [123], with the decrease in apoC-III being associated with the decrease in plasma triacylglycerol concentrations. In a 16-week randomized controlled dietary intervention study, weight loss was associated with an 18% reduction in apoC-III concentrations in men with the metabolic syndrome (Ng, T.W.K., Barrett, P.H.R., Chan, D.C. and Watts, G.F., unpublished work). The reduction in plasma apoC-III with weight loss was associated with decreases in insulin, triacylglycerols, apoB-48, VLDL-apoB and RLP (remnant-like protein)-cholesterol. The underlying mechanism of action of weight loss on apoC-III metabolism requires further study, but it is likely to be associated with improved insulin sensitivity and reduced hepatic secretion of apoC-III. Dietary composition has also been demonstrated to have varying effects on plasma apoC-III concentrations [124126] (Table 2). Consumption of diets high in MUFAs (monosaturated fatty acids) resulted in a significant reduction in plasma apoC-III and fasting triacylglycerol levels [57]. By contrast, a low-fat and high-carbohydrate diet was associated with increased apoC-III and triacylglycerol concentrations [127]. The hypotriglyceridaemic effect of a high-MUFA diet may be attributable, in part, to reduced hepatic apoC-III production [57]. Studies also suggest that alcohol consumption increased total and apoC-III-non-LpB and decreased apoC-III-LpB [128]. Further studies are required to elucidate the regulatory effect of alcohol on apoC-III metabolism. The effect of exercise on apoC-III metabolism has yet to be examined and warrants further study.

Other therapies

The use of siRNA (small interfering RNA) directed at inhibiting the translation of apoB mRNA has attracted much recent attention as a highly effective approach for treating dyslipidaemia [129]. Further investigations are warranted to determine whether this antisense technology may be applied to inhibit apoC-III synthesis and to treat the associated dyslipidaemia.

CONCLUSIONS

Elevated plasma triacylglycerol concentrations have been recently identified as powerful predictors of CVD in diverse populations. Abnormal metabolism of apoC-III, a small-molecular-mass peptide, may form the basis for this relationship. Recent studies also provide evidence for a direct role of apoC-III in atherogenesis, supporting the findings in clinical studies that elevated apoC-III are independent predictors of coronary events in high risk individuals. ApoC-III metabolism is a complex physiological system that needs to be elucidated further using tracer methods and systems analysis. In time, apoC-III may become a new target for interventions, particularly in subjects with insulin resistance, the metabolic syndrome and Type 2 diabetes. Future studies are required to establish the therapeutic target for apoC-III and the practical aspects of its routine assay in the laboratory.

Abbreviations

     
  • apo

    apolipoprotein

  •  
  • apoC-III-LpB

    apoC-III associated with apoB-containing lipoproteins

  •  
  • apoC-III-non-LpB

    apoC-III associated with non-apoB-containing lipoproteins

  •  
  • CARE

    Cholesterol and Recurrent Events

  •  
  • CETP

    cholesteryl ester transfer protein

  •  
  • CLAS

    Cholesterol-Lowering Atherosclerosis Study

  •  
  • CVD

    cardiovascular disease

  •  
  • ECTIM

    Etude Cas-Temoin de l'Infarctus du Myocarde

  •  
  • FXR

    farnesoid X receptor

  •  
  • HDL

    high-density lipoprotein

  •  
  • HL

    hepatic lipase

  •  
  • HMG-CoA

    3-hydroxy-3-methylglutaryl-CoA

  •  
  • ICAM-1

    intracellular adhesion molecule-1

  •  
  • IEF

    isoelectric focusing

  •  
  • IRE

    insulin-response element

  •  
  • LCAT

    lecithin cholesterol acyltransferase

  •  
  • LDL

    low-density lipoprotein

  •  
  • LDLR

    LDL receptor

  •  
  • LpB:C-III

    concentration of apoB-containing particles that contain apoC-III

  •  
  • LPL

    lipoprotein lipase

  •  
  • LSR

    lipolysis-stimulated receptor

  •  
  • MARS

    Monitored Atherosclerosis Regression Study

  •  
  • MUFA

    monosaturated fatty acid

  •  
  • NF-κB

    nuclear factor κB

  •  
  • PPAR

    peroxisome-proliferator-activated receptor

  •  
  • RXR

    retinoid X receptor

  •  
  • TRL

    triacylglycerol-rich lipoprotein

  •  
  • VCAM-1

    vascular cell adhesion molecule-1

  •  
  • VLDL

    very-low-density lipoprotein

We thank Professor Frank M. Sacks (Nutrition Department, Harvard School of Public Health, Boston, MA, U.S.A.) for providing Figure 6. E.M.M.O. is a Research Fellow of the National Heart Foundation of Australia (PF07P3263). P.H.R.B. is a Research Fellow of the National Health and Medical Research Council and is supported, in part, by the National Institutes of Health (NIH/NIBIB P41 EB-001975). D.C.C. is supported by an NHMRC Career Development Award.

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