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

High-density 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 composition of proteins and lipids determining HDL functionality) may be more important than their quantity. The functionality of HDL is mirrored by its cholesterol efflux activity, as well as its antioxidant (including the protection of LDL against oxidation), anti-inflammatory and antithrombotic properties. The results of many studies and meta-analyses imply the beneficial 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 beneficial impact on HDL particle maturation, composition 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.

Genetically determined deficiency of ANGPTL3 does not alter HDL ability to preserve endothelial homeostasis.

Individuals with loss-of-function mutations in the ANGPTL3 gene express a rare lipid phenotype called Familial Combined Hypolipidemia (FHBL2). FHBL2 individuals show reduced plasma concentrations of total cholesterol and triglycerides as well as of lipoprotein particles, including HDL. This feature is particularly remarkable in homozygotes in whom ANGPTL3 in blood is completely absent. ANGPTL3 acts as a circulating inhibitor of LPL and EL and it is thought that EL hyperactivity is the cause of plasma HDL reduction in FHBL2. Nevertheless, the consequences of ANGTPL3 deficiency on HDL functionality have been poorly explored. In this report, HDL isolated from homozygous and heterozygous FHBL2 individuals were evaluated for their ability to preserve endothelial homeostasis as compared to control HDL. It was found that only the complete absence of ANGPTL3 alters HDL subclass distribution, as homozygous, but not heterozygous, carriers have reduced content of large and increased content of small HDL with no alterations in HDL2 and HDL3 size. The plasma content of preß-HDL was reduced in carriers and showed a positive correlation with plasma ANGPTL3 levels. Changes in composition did not however alter the functionality of FHBL2 HDL, as particles isolated from carriers retained their capacity to promote NO production and to inhibit VCAM-1 expression in endothelial cells. Furthermore, no significant changes in circulating levels of soluble ICAM-1 and E-selectin were detected in carriers. These results indicate that changes in HDL composition associated with the partial or complete absence of ANGPTL3 did not alter some of the potentially anti-atherogenic functions of these lipoproteins.

Associations of HDL metrics with coronary artery calcium score and density among women traversing menopause.

The cardioprotective association of high-density lipoprotein cholesterol (HDL-C) may vary by menopause stage or estradiol level. We tested whether associations of comprehensive HDL metrics (HDL subclasses, phospholipid and triglyceride content, and HDL cholesterol efflux capacity [HDL-CEC]) with coronary artery calcium (CAC) score and density vary by menopause stage or estradiol level in women transitioning through menopause. Participants (N = 294; mean age [SD]: 51.3 [2.9]) had data on HDL metrics and CAC measures at one or two time points during the menopause transition. Generalized estimating equations were used for analyses. Effect modifications by menopause stage or estradiol level were tested in multivariable models. In adjusted models, menopause stage modified the associations of specific HDL metrics with CAC measures. Higher small HDL particles (HDL-P) concentrations (p-interaction = 0.008) and smaller HDL size (p-interaction = 0.02) were associated with greater odds of CAC presence in late perimenopause than in pre/early perimenopause stage. Women in the highest estradiol tertile, but not the lower tertiles, showed a protective association of small HDL-P with CAC presence (p-interaction = 0.007). Lower large HDL-P concentrations (p-interaction = 0.03) and smaller HDL size (p-interaction = 0.03) were associated with lower CAC density in late perimenopause than in postmenopause stage. Associations of HDL phospholipid and triglyceride content and HDL-CEC with CAC measures did not vary by menopause stage or estradiol level. We concluded that HDL subclasses may impact the likelihood of CAC presence and the stability of coronary plaque differently over the menopause transition. Endogenous estradiol levels may contribute to this observation.

rHDL modeling and the anchoring mechanism of LCAT activation.

Lecithin:cholesterol-acyl transferase (LCAT) plays a major role in cholesterol metabolism as it is the only extracellular enzyme able to esterify cholesterol. LCAT activity is required for lipoprotein remodeling and, most specifically, for the growth and maturation of HDLs. In fact, genetic alterations affecting LCAT functionality may cause a severe reduction in plasma levels of HDL-cholesterol with important clinical consequences. Although several hypotheses were formulated, the exact molecular recognition mechanism between LCAT and HDLs is still unknown. We employed a combination of structural bioinformatics procedures to deepen the insights into the HDL-LCAT interplay that promotes LCAT activation and cholesterol esterification. We have generated a data-driven model of reconstituted HDL (rHDL) and studied the dynamics of an assembled rHDL::LCAT supramolecular complex, pinpointing the conformational changes originating from the interaction between LCAT and apolipoprotein A-I (apoA-I) that are necessary for LCAT activation. Specifically, we propose a mechanism in which the anchoring of LCAT lid to apoA-I helices allows the formation of a hydrophobic hood that expands the LCAT active site and shields it from the solvent, allowing the enzyme to process large hydrophobic substrates.

Exercise intervention alters HDL subclass distribution and function in obese women.

BACKGROUND: Obesity is associated with a change in high-density lipoprotein (HDL) function and subclass. Exercise training reduces cardiovascular risk in obese patients. We aimed to explore the effect of an exercise training stimulus on HDL functionality and subclass in obese women. METHODS: Thirty-two obese black South African women were randomly assigned to exercise (combined aerobic and resistance exercise) or control (no exercise) conditions for 12-weeks. Pre- and post-testing included venous blood sampling for analysis of lipid profile and HDL functionality, by measuring cellular cholesterol efflux capacity, reduction in endothelial vascular cell adhesion molecule (VCAM) expression (anti-inflammatory function), paraoxonase (PON) (antioxidative function) and platelet activating factor acetylhydrolase (PAF-AH) activities (anti-thrombotic function). PON-1 and PAF-AH expression were determined in serum and in isolated HDL using Western blotting. Levels of large, intermediate and small HDL subclasses were measured using the Lipoprint® system. RESULTS: Exercise training resulted in a decrease in body mass index (- 1.0 ± 0.5% vs + 1.2 ± 0.6%, p = 0.010), PON activity (- 8.7 ± 2.4% vs + 1.1 ± 3.0%, p = 0.021), PAF-AH serum expression (- 22.1 ± 8.0% vs + 16.9 ± 9.8, p = 0.002), and the distribution of small HDL subclasses (- 10.1 ± 5.4% vs + 15.7 ± 6.6%, p = 0.004) compared to controls. Exercise did not alter HDL cellular cholesterol efflux capacity and anti-inflammatory function. CONCLUSIONS: These results demonstrate the potential for exercise training to modify HDL subclass distribution and HDL function in obese women. TRIAL REGISTRATION: Clinical trials number: PACTR201711002789113 .

Plasma cholesterol homeostasis, HDL remodeling and function during the acute phase reaction.

Acute phase reaction (APR) is a systemic inflammation triggered by several conditions associated with lipid profile alterations. We evaluated whether APR also associates with changes in cholesterol synthesis and absorption, HDL structure, composition, and cholesterol efflux capacity (CEC). We analyzed 59 subjects with APR related to infections, oncologic causes, or autoimmune diseases and 39 controls. We detected no difference in markers of cholesterol synthesis and absorption. Conversely, a significant reduction of LpA-I- and LpAI:AII-containing HDL (-28% and -44.8%, respectively) and of medium-sized HDL (-10.5%) occurred in APR. Total HDL CEC was impaired in APR subjects (-18%). Evaluating specific CEC pathways, we found significant reductions in CEC by aqueous diffusion and by the transporters scavenger receptor B-I and ABCG1 (-25.5, -41.1 and -30.4%, respectively). ABCA1-mediated CEC was not affected. Analyses adjusted for age and gender provided similar results. In addition, correcting for HDL-cholesterol (HDL-C) levels, the differences in aqueous diffusion total and ABCG1-CEC remained significant. APR subjects displayed higher levels of HDL serum amyloid A (+20-folds; P = 0.003). In conclusion, APR does not associate with cholesterol synthesis and absorption changes but with alterations of HDL composition and a marked impairment of HDL CEC, partly independent of HDL-C serum level reduction.

A Tribute to the Philadelphia Lipid Group on the Occasion of Their Retirement.

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