The Impact of Aerobic Exercise on HDL Quantity and Quality: A Narrative Review

sity lipoproteins comprise roughly 25–30% of the circulating proteins involved in the transport of lipids in circulation. These particles differ in size and lipid composition. Recent evidence suggests that the quality of HDL particles (which depends on shape, size and the com- position of proteins and lipids determining HDL functionality) may be more important than their quantity. The functionality of HDL is mirrored by its cholesterol ef ux activity, as well as its antiox- idant (including the protection of LDL against oxidation), anti-in ammatory and antithrombotic properties. The results of many studies and meta-analyses imply the bene cial impact of aerobic exercise on HDL-C levels. Physical activity was found to be usually associated with an increase in HDL cholesterol and a decrease in LDL cholesterol and triglycerides. Exercise, apart from inducing quantitative alterations in serum lipids, exerts a bene cial impact on HDL particle maturation, com- position and functionality. The Physical Activity Guidelines Advisory Committee Report underlined the importance of establishing a program recommending exercises

Physical activity was found to be usually associated with an increase in HDL cholesterol and a decrease in LDL cholesterol and triglycerides. Exercise, apart from inducing quantitative alterations in serum lipids, exerts a bene cial impact on HDL particle maturation, com- position and functionality. The Physical Activity Guidelines Advisory Committee Report underlined the importance of establishing a program recommending exercises that enable attainment of maximal advantage at the lowest level of risk. The aim of this manuscript is to review the impact of different types of aerobic exercise (various intensities and durations) on the level and quality of HDL. Keywords: aerobic exercise; HDL levels; HDL structure; HDL functioning; training intensity; training duration 1. Introduction High-density lipoproteins (HDL) comprise roughly 25–30% of the circulating proteins involved in the transport of lipids in circulation [1]. These particles have a complex structure; they are of different sizes and lipid compositions. Both the quantity and quality of HDL appear to be in uenced by aging, disease states, exposure to some environmental factors (e.g., pollutants) and pathogens, smoking and diet [2]. Therefore, the level of HDL cholesterol uctuates during our lifetime [3,4]. Moreover, according to studies, a sedentary lifestyle is related to low HDL levels, irrespective of age and sex [5,6]. Low HDL levels are usually accompanied by high triglyceride (TG) levels, insulin resistance and abdominal obesity [7]. However, in individuals with hypoalphalipoproteinemia, relatively normal total lipids and decreased HDL cholesterol (HDL-C) are observed [8]. In the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study, men with isolated HDL also had very low mean plasma cholesterol, low-density lipoprotein (LDL), apolipoprotein B (apoB) and apoA-I levels [9]. They were not obese, and their abdominal fat accumulation did not differ from normolipidemic individuals. HDL cholesterol, apart from being involved in reverse transport, exerts various effects, including anti-in ammatory, antioxidative, antidiabetic, antithrombotic, and many activities [10]. The results of studies have demonstrated that isolated low HDL cholesterol may translate into a greater risk of Int. J. Mol. Sci.2023,24, 4653.

apart from being involved in reverse transport, exerts various effects, including anti-in ammatory, antioxidative, antidiabetic, antithrombotic, and many activities [10]. The results of studies have demonstrated that isolated low HDL cholesterol may translate into a greater risk of Int. J. Mol. Sci.2023,24, 4653.

Int. J. Mol. Sci.2023,24, 4653 2 of 23 coronary heart disease (CHD) [11]. Reduced plasma levels of HDL cholesterol are a common abnormality reported in patients with CHD [12]. The results of randomized, controlled drug trials have demonstrated that a pharmacological increase in HDL levels does not translate into ameliorated cardiovascular disease (CVD) outcomes [13–15]. Therefore, later interventions are focused on the improvement of the quality and functionality of HDL, not only its levels. It has been suggested that exercise, especially aerobic exercise, may have the potential to improve the atheroprotective functions of HDL [16]. The results of studies and meta-analyses have suggested the bene cial impact of aerobic exercise on HDL-C levels [2,5]. Regular exercise and a healthy diet are considered to be crucial for the maintenance of a normal lipid pro le and subsequent reduction in cardiovascular risk [16]. Available evidence indicates that acute and chronic aerobic exercise may increase plasma levels of HDL cholesterol in a dose-dependent manner [17,18]. The aim of this manuscript is to review the impact of different types of aerobic exercise (various intensities and durations) on the level and quality of HDL. We conducted a PubMed search to identify articles suitable for inclusion in this narrative review. We did not perform a systematic review. Terms that were searched for included “Aerobic exercise”, “HDL structure”, “HDL levels”, “HDL functioning”, “chronic exercise”, “acute exercise”, “low-moderate intensity training” and “high intensity training”. 2. Structure and Functions of HDL Cholesterol HDL particles are very heterogenous and can be subdivided into several subclasses with distinct functionalities [19]. The division of HDL into subclasses depends on the method of separation. In the literature, HDL is most frequently subdivided into two principal HDL subclasses via ultracentrifugation, i.e., HDL2 (larger particles) and HDL3 (smaller particles) [20–22]. HDL2 can be further divided into HDL2a and HDL2b. These subfractions contain higher amounts of cholesterol, and their role in reverse cholesterol transport is more pronounced. In turn, HDL3 is a more nascent form of HDL that contains less cholesterol and shows higher density compared to HDL2 [19,22]. With the use of the Lipoprint system,

and HDL3 (smaller particles) [20–22]. HDL2 can be further divided into HDL2a and HDL2b. These subfractions contain higher amounts of cholesterol, and their role in reverse cholesterol transport is more pronounced. In turn, HDL3 is a more nascent form of HDL that contains less cholesterol and shows higher density compared to HDL2 [19,22]. With the use of the Lipoprint system, it is possible to obtain as many as 10 HDL subfractions that belong to 3 subclasses: large, intermediate and small. HDL particles possess atheroprotective properties since they participate in reverse cholesterol transport [16]. Reverse cholesterol transport involves the transfer of periph- eral cholesterol to HDL particles and its transportation to the liver for excretion. The initial step of this process, macrophage-speci c cholesterol ef ux, appears to be crucial for HDL-related protection against atherosclerosis [16]. ATP binding cassette A-1 receptor (ABCA-1) is involved in the taking up of cholesterol from macrophages in the artery wall by nascent HDL [23]. In the early stage of cholesterol ef ux, lipid-free apoA-I attaches to cholesterol, forming discoidal HDL [2]. In the next stages, more free cholesterol be- comes bound, and lecithin:cholesterol acyltransferase (LCAT) catalyzes its esteri cation to cholesteryl ester (CE), which leads to the formation of a core of spherical HDL. Following the binding with phospholipid (PL), free cholesterol (FC) and apoA-I form disc-shaped HDL particles, which subsequently undergo growth and maturation. The transformation of discoidal HDL into spherical HDL is associated with greater cholesterol ef ux and the formation of cholesteryl ester. The process of HDL maturation involves the accumula- tion of cholesteryl ester. During this step, smaller HDL3 particles grow to form larger HDL2 particles enriched with cholesterol with a larger particle size [2]. The role of reverse cholesterol transport in cardiovascular protection has been con rmed in numerous animal and human studies. Apart from its role in reverse cholesterol ef ux, HDL cholesterol also possesses other important physiological properties, such as anti-in ammatory, antioxida- tive and antithrombotic effects, which are partly mediated by bound enzymes [24]. The functionality of HDL is partly associated with the presence of various protein

in cardiovascular protection has been con rmed in numerous animal and human studies. Apart from its role in reverse cholesterol ef ux, HDL cholesterol also possesses other important physiological properties, such as anti-in ammatory, antioxida- tive and antithrombotic effects, which are partly mediated by bound enzymes [24]. The functionality of HDL is partly associated with the presence of various protein and lipid compounds. Apolipoprotein A-I is a vital HDL protein, the content of which may reach 70% and which appears to be responsible for the anti-in ammatory and antioxidant properties of HDL [2,25]. This protein is also involved in cholesterol ef ux activity [26]. ApoA-I

Int. J. Mol. Sci.2023,24, 4653 3 of 23 contributes to HDL quality; therefore, its diminished content is considered a risk factor for cardiovascular events [2]. ApoA-II is the second most crucial HDL apolipoprotein. Its increased serum levels have been suggested to be related to combined hyperlipidemia, higher indices of atherogenic lipoproteins and atherosclerosis development [26,27]. The results of studies demonstrated that higher content of apoA-II in HDL was associated with paraoxonase displacement from the particle and decreased HDL antioxidant properties [28]. Moreover, apoA-II could affect the interaction of HDL with scavenger receptor-B-I (SR-BI) and impair HDL functioning via the involvement of apoA-I displacement in a reconstituted HDL [29]. The enrichment of HDL particles in apoC-III may also cause functional and structural impairment of HDL, leading to the acquisition of more atherogenic properties by HDL. Higher content of apoC-III is associated with the senescence-related truncation of apoA-I and greater HDL glycation [30]. The results ofin vitrostudies indicate that higher apoC-III and decreased content of apoA-I in HDL may be related to the formation of dysfunctional HDL [31,32]. Furthermore, apoC-III was suggested to induce alternative in ammasome activation, leading to organ damage and subsequently enhanced mortality, especially in patients with chronic kidney disease and acute myocardial infarction [33]. Human serum amyloid A (SAA) is another particle associated with HDL in the plasma, especially dysfunctional HDL. The roles of lipid-free and HDL-associated forms of SAA are different [34]. Lipid-free SAA plays a role in innate immunity and the repair of tissues. It has been found to be involved in in ammatory cytokine induction, the chemotaxis of leuko- cytes and the upregulation of genes regulating extracellular matrix remodeling [35–37]. However, these actions appear to be mostly abrogated if the SAA is attached to HDL [38]. The enhanced incorporation of this acute-phase reactant has been demonstrated to indicate ongoing systemic in ammation [39]. SAA-enriched HDL is susceptible to releasing lipid- free apoA-I, thereby promoting the formation of poor-quality HDL [40]. Dullaart et al. [41] demonstrated that the antioxidative properties of HDL are inversely correlated with the level of circulating SAA in patients with metabolic syndrome.

[38]. The enhanced incorporation of this acute-phase reactant has been demonstrated to indicate ongoing systemic in ammation [39]. SAA-enriched HDL is susceptible to releasing lipid- free apoA-I, thereby promoting the formation of poor-quality HDL [40]. Dullaart et al. [41] demonstrated that the antioxidative properties of HDL are inversely correlated with the level of circulating SAA in patients with metabolic syndrome. Therefore, it seems that higher SAA concentrations may hamper the antioxidative activity of HDL [39]. Lipids contained in HDL particles, for example, triglycerides and cholesterol, also affect the quality of HDL [2]. Higher content of cholesterol in HDL is associated with larger particle size, while increased content of TG results in the formation of smaller particles and impaired HDL functionality, which leads to disturbed cholesterol transport and ef ux. The results of studies have revealed that decreased content of cholesterol and higher content of TG in HDL particles increase the risk of metabolic syndrome. Highly functional HDL parti- cles are large, with a distinct round shape, and they contain a high amount of apoA-I [2]. Several enzymes are associated with HDL particles, including an esterase paraoxonase 1 (PON1), platelet-activating factor acetylhydrolase (PAF-AH) and LCAT. Paraoxonase 1 is involved in the antioxidative activities of HDL particles, while PAF-AH participates in antithrombotic actions [42,43]. Paraoxonase-displaying lactonase and ester hydrolase activity can degrade lipid peroxides in LDL and hinder viral infections [2,44]. In a healthy state, native HDL protects LDL from oxidation since it neutralizes free radicals and reactive oxygen species (ROS), but it is also involved in the transport of oxidized LDL (oxLDL) to the liver for excretion. The process of atherosclerosis is associated with the presence of oxidative stress and the subsequent formation of oxidized LDL cholesterol. OxLDLs are potent triggers of atherosclerosis, and their presence is associated with an increased risk of cardiovascular diseases and cerebrovascular diseases [45,46]. HDL cholesterol hampers the oxidation of LDL via the metabolization of lipid hydroperoxides, thereby limiting their accumulation on low-density lipoproteins [47]. The results of studies have demonstrated that HDL is also capable of taking up lipid peroxides and transporting them to the

of atherosclerosis, and their presence is associated with an increased risk of cardiovascular diseases and cerebrovascular diseases [45,46]. HDL cholesterol hampers the oxidation of LDL via the metabolization of lipid hydroperoxides, thereby limiting their accumulation on low-density lipoproteins [47]. The results of studies have demonstrated that HDL is also capable of taking up lipid peroxides and transporting them to the liver for excretion [48]. The vasoprotective activity of HDL is primarily associated with the stimulation of endothelial production of nitric oxide, which exerts vasodilatory effects [39]. Some disease states are associated with the presence of dysfunctional HDL with altered properties. HDL quality and functionality can be impaired by many stressors, including aging, smoking, pollutants, infection and unhealthy food habits [2]. Dysfunctional HDL

Int. J. Mol. Sci.2023,24, 4653 4 of 23 contains lower amounts of cholesterol; it is also enriched with TG, SAA and apoC-III, and the displacement of apoA-I is observed. These changes result in the alteration of HDL particle morphology, with particles becoming smaller in size and taking on an ambiguous shape due to exposure to glycation stress, oxidative stress, smoking, etc. The results of studies have demonstrated that generally, females tend to have higher plasma HDL-C and lower LDL-C and TG levels than males [49–51]. However, it appears that HDL mean particle size is larger in women ( 85 Å) than in men (<85 Å). Williams et al. [21] observed increased concentrations of HDL3b in post-menopausal women, as well as considerably higher HDL3c and HDL3b and signi cantly lower HDL2b and HDL2a levels in adult men than boys (<18 years). The levels of HDL3c and HDL3b are higher in adult than women, while the levels of HDL2b, HDL2a and larger-diameter HDL3a particles are lower in males. These results may indicate the impact of sex hormones on the determination of HDL levels. It has been suggested that the association between hormones, plasma HDL-C concentration and lipoprotein particles size is more complex and also involves visceral adipose tissue [50]. Both plasma concentrations of HDL and HDL size appear to be regulated by plasma triglyc- eride concentrations, lipase activities, insulin sensitivity and abdominal fat via their effect on the apoA-I fractional catabolic rate (FCR) [52]. Females were found to have lower FCR of apo A-I and apo A-II than men. FCR of apo A-I is the principal metabolic mechanism responsible for increased HDL cholesterol, and its low values are related to a lipid-rich HDL fraction [53]. The impact of hormones (estradiol) on increased HDL and apoA-I levels was con rmed in a study of a cohort of young transgender individuals (phenotypical males treated with puberty blockers followed by estradiol) [54]. The estradiol-related increase in HDL level was found to be dose-dependent and chromosome-independent, which implies that compared to atherogenic lipoproteins, HDL may be more sensitive to uctuation of hormones levels at a young

HDL and apoA-I levels was con rmed in a study of a cohort of young transgender individuals (phenotypical males treated with puberty blockers followed by estradiol) [54]. The estradiol-related increase in HDL level was found to be dose-dependent and chromosome-independent, which implies that compared to atherogenic lipoproteins, HDL may be more sensitive to uctuation of hormones levels at a young age. This study also indicated the in uence of testosterone on increased very low-density lipoprotein (VLDL) levels in trans men (young phenotypical females treated with puberty blockers followed by testosterone). The presence of obesity, diabetes mellitus and metabolic syndrome has been demon- strated to affect the lipoprotein pro le. Obese individuals show a reduction in plasma HDL-C levels, as well as an increase in TG [55,56]. In obese individuals, the contents of apoA-I, cholesterol and phospholipid levels in HDL are decreased, while levels of serum amyloid are increased. This translates into a shift towards smaller HDL3 subclasses and reduced HDL2 and antioxidative capacity. The level of the HDL3 subfraction is strongly correlated with lecithin cholesterol acyltransferase (LCAT) activity. Such alterations were not observed in overweight females [55]. However, in overweight women, only TG content in HDL was increased. Stadler et al. [55] reported signi cant alterations in the activity of cholesteryl ester transfer protein (CETP) (involved in conversion of lipid-poor pre- particles to HDL3) and LCAT and modi ed HDL composition. In obese women, the ac- tivity of cholesterol ester transfer protein (CETP) enzyme involved in HDL metabolism was reported to be increased, in agreement with the fact that adipose tissue synthesizes large amounts of CETP [57,58]. In obese women, LCAT activity and protein levels also appear to be signi cantly increased and correlate with reduced antioxidative capacity of HDL [55,59]. A similar relationship was demonstrated in diabetic females [55]. The increase in LCAT activity in obesity and obesity-associated low-grade in ammation may represent a compensatory mechanism [60,61]. According to Stadler et al. [55], enhanced activity of LCAT in obese females translates into increased formation of cholesteryl esters in HDL. Successive CETP-mediated transfer to triglyceride-rich lipoproteins in exchange for triglyc-

[55,59]. A similar relationship was demonstrated in diabetic females [55]. The increase in LCAT activity in obesity and obesity-associated low-grade in ammation may represent a compensatory mechanism [60,61]. According to Stadler et al. [55], enhanced activity of LCAT in obese females translates into increased formation of cholesteryl esters in HDL. Successive CETP-mediated transfer to triglyceride-rich lipoproteins in exchange for triglyc- erides leads to higher triglyceride content in HDL, accelerated HDL hydrolysis by hepatic and lipoprotein lipases and, eventually, to the formation of smaller, denser HDL3 particles, as well as decreased HDL2 cholesterol levels [62,63]. Davidson et al. [64] observed that obesity partly explained variability in HDL at the subspecies levels. This nding was con rmed in a study in which weight loss surgery reversed the atherogenic HDL pro le previously observed in obese patients. Within one year of the surgery, an increase in larger HDL particles and a loss of small HDL particles were reported [65]. However, this effect

This review discusses the impact of aerobic exercise on HDL levels and quality.