HDL Cholesterol Efflux Capacity: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 3 by Francesca Zimetti.

Over the years, the relationship between high-density lipoprotein (HDL) and atherosclerosis, initially highlighted by the Framingham study, has been revealed to be extremely complex, due to the multiple HDL functions involved in atheroprotection. Among them, HDL cholesterol efflux capacity (CEC), the ability of HDL to promote cell cholesterol efflux from cells, has emerged as a better predictor of cardiovascular (CV) risk compared to merely plasma HDL-cholesterol (HDL-C) levels. HDL CEC is impaired in many genetic and pathological conditions associated to high CV risk such as dyslipidemia, chronic kidney disease, diabetes, inflammatory and autoimmune diseases, endocrine disorders, etc. 

  • reverse cholesterol transport
  • high density lipoprotein
  • cholesterol efflux capacity
  • atherosclerosis
  • cardiovascular disease

1. Introduction

High-density lipoprotein cholesterol (HDL-C) has been considered for years the “good” cholesterol, as suggested by the inverse correlation between its plasma levels and the cardiovascular (CV) risk, as shown by the epidemiology [1][2]. However, the relationship between HDL and atherosclerosis was found to be much more complex compared, for example, to that observed for low density lipoproteins (LDL). Firstly, a recent study has revealed a paradoxical association between very high HDL-C levels and increased CV disease (CVD) [3]. In addition, the failure of the trials testing the HDL-C raising drugs, together with the results of genetic studies on several polymorphisms or rare mutations, have led to some shadow being cast on the “HDL hypothesis” [4][5][6].

In parallel, a growing interest pointed to the importance of the HDL function in the context of atheroprotection. In facts, HDL possess several functions, among which the best known is the ability to promote the first step of the reverse cholesterol transport (RCT) process, namely the cholesterol efflux from the macrophages of the arterial wall [7][8].

Cell cholesterol efflux may occur through multiple mechanisms including aqueous diffusion, as well as facilitated and active transport both promoted by specific membrane proteins, such as the scavenger receptor class B, type I (SR-BI) and members of the ATP binding cassette (ABC) transporter family, ABCG1 and ABCA1, respectively [9]. The ability of HDL to promote cell cholesterol efflux (cholesterol efflux capacity, CEC) appears to be more related to HDL size and composition in terms of proteins and lipids, than to HDL-C plasma levels. CEC is usually evaluated by radioisotopic or fluorimetric bioassays in which cells are exposed to the HDL serum fraction, obtained by depletion of serum of the apolipoprotein (apo)B-containing lipoproteins. Such evaluation has emerged as a potentially accurate estimate of the RCT efficiency in humans [10].

The clinical relevance of HDL CEC is well highlighted by many studies, in which an inverse relationship was detected between CEC and the prevalence of atherosclerosis, as well as the incidence of CV events, occurring independently of plasma HDL-C levels [11]. In addition, CEC has been found to be impaired in several genetic disorders leading to dyslipidemia, as well as in specific pathological conditions associated to higher CV risk, such as chronic kidney disease, diabetes, inflammatory and autoimmune diseases, endocrine disorders etc.

2. HDL and RCT

HDL was discovered in the 1950s and in 1960s the Framingham Heart Study reported the inverse relationship between plasma levels of these lipoproteins and atherosclerosis [1]. This milestone discovery encouraged investigations of the mechanism by which HDL could exert their anti-atherogenic properties, leading to the identification of the RCT process [12]. RCT, proposed for the first time by Glomset, is the key physiological pathway by which excess cholesterol is removed from the peripheral tissues to the liver for the final excretion into the bile and feces [12]. RCT may prevent the formation and progression of atherosclerotic plaque through the HDL-mediated removal of cholesterol from the arterial wall, identified as the main anti-atherogenic mechanism of HDL.

This process could be outlined in three phases:

  • Cellular cholesterol efflux from macrophages;

  • HDL remodeling in plasma;

  • Cholesterol hepatic uptake and excretion.

2.1. Cellular Cholesterol Efflux from Macrophages

In the first step, cholesterol is initially moved from arterial macrophages to extracellular HDL [13]. This is the rate-limiting step of the entire RCT process [13] and plays a pivotal role in the maintenance of intracellular cholesterol homeostasis, crucial for macrophage function and viability. The excess of free cholesterol (FC) is toxic for cells, and this may be a very important factor considering that most peripheral cells and tissues (except for those of steroidogenic organs) cannot catabolize cholesterol. For this reason, macrophages protect themselves against FC accumulation by either transforming it to cholesteryl esters (CE) for intracellular storage or by effluxing it to extracellular acceptors such as HDL [14]. Cholesterol efflux mainly depends on macrophage cholesterol content, on the expression of various macrophage cholesterol transporters that mediate efflux and also on the features of the HDL acting as extracellular acceptors, mainly in terms of lipid and protein composition, as well as size [15][16].

2.2. HDL Remodeling in Plasma

In the subsequent RCT steps, cholesterol-enriched HDL may undergo remodeling in size and composition through the activity of the two enzymes lecithin-cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP). LCAT, synthetized in the liver, is the only enzyme able of esterifying FC of HDL to CE, transforming nascent discoidal particles in spherical HDL. The preferential lipoprotein substrates for LCAT are the discoidal preβ-HDL, produced through the initial interaction of lipid-free apolipoprotein A-I (apoA-I) with the ABCA1 transporter, with consequent cellular efflux of FC and phospholipids [17]. By esterifying HDL cholesterol, the enzyme LCAT helps to maintain the unesterified cholesterol gradient between the cell membrane and the extracellular acceptors, determining a constant flux of cholesterol from periphery to circulating lipoproteins and avoiding cholesterol reuptake by cells [18]. Despite its central function in HDL remodeling and maturation, the role of LCAT in the pathogenesis of atherosclerosis is still debated. In mice, the overexpression of human LCAT increased circulating HDL levels, but did not enhance macrophage RCT. Moreover, a significant macrophage RCT emerged in LCAT-deficient mice despite extremely low plasma levels of HDL-C [19]. Existing data in humans are controversial, but markedly support the idea that decreased LCAT concentration and activity, despite reducing HDL levels, are not related with the pathogenesis of atherosclerosis [17]. In particular, a study by our group demonstrated that serum from LCAT deficiency patients display increased ABCA1-mediated capacity to promote cholesterol efflux compared to control subjects, due to the presence of high levels of preβ-HDL [20].

The second enzyme playing a key role in RCT is CETP. This enzyme is an hydrophobic glycoprotein mainly produced by the liver, circulating in plasma largely bound to HDL [21]. It promotes the net mass transfer of CE from anti-atherogenic HDL to pro-atherogenic apoB)containing lipoproteins, in exchange with triglycerides (TG). Human studies have generally supported the idea that CETP deficiency, associated with increased HDL and apoA-I levels, is anti-atherogenic. This hypothesis has paved the way for developing CETP inhibitors as a possible strategy to raise HDL levels in humans, to reduce atherosclerosis and to treat CVD [22]. In human studies, CETP inhibition indeed induced an increase in HDL-C together with a decrease in the non-HDL-C. Nevertheless, clinical studies have failed in proving their capacity to reduce CV risk [23].

2.3. Cholesterol Hepatic Uptake and Excretion

In the third step of RCT, free and esterified HDL-derived cholesterol are uptaken by hepatocytes through the transporter SR-BI, generating cholesterol-poor HDL that can be recycled [24]. Moreover, in addition to the major pathway via SR-BI, under some conditions, HDL can be recognized also by LDL receptors (LDLr) in the liver, as observed in mice [25]. In addition, a recent study supported a novel concept suggesting that, at least in mice, a shift in macrophage-derived unesterified cholesterol from HDL to LDL provides a significant route for macrophage cholesterol to reach the liver via the hepatic LDLr [26].

After hepatic uptake, cholesterol can be eliminated into the bile as neutral sterols via the transporters ABCG5/ABCG8 or through ABCA1, after conversion into bile acids, and excreted via faeces [27]. For many years, the hepatobiliary route has been considered the only way for cholesterol excretion. Conversely, in recent years another metabolic pathway has been discovered. This mechanism, known as trans-intestinal cholesterol excretion, takes place directly from plasma to the lumen of the intestine and markedly contributes to the total fecal neutral sterol excretion 

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