Alterations in the High Density Lipoprotein Phenotype and HDL‐Associated Enzymes in Subjects with Metabolic Syndrome

Abstract

Patients with metabolic syndrome (MetS) usually have low high density lipoprotein cholesterol (HDL-C) levels. We determined the HDL distribution profile as well as the HDL-related lipoprotein associated phospholipase A(2) (HDL-LpPLA(2)) and paraoxonase-1 (PON1) activities in subjects with MetS (n = 189) but otherwise healthy. Age and sex-matched individuals (n = 166) without MetS served as controls. The lower HDL-C concentration in MetS patients was due to a reduction in both large and small HDL subclasses (P < 0.001 and P < 0.05, respectively). As the number of MetS components increased, the HDL phenotype comprised of a greater percentage of small HDL-3 and less large HDL-2 subclasses, resulting in a decreased HDL-2/HDL-3 ratio (P < 0.001 for all trends). Multivariate analysis revealed that HDL-2 levels and the HDL-2/HDL-3 ratio significantly and independently correlated with HDL-C (positively) and TG (negatively) levels. HDL-3 concentration significantly and independently positively correlated with HDL-C and TG levels. HDL-LpPLA(2) activity was decreased in MetS patients (P < 0.01), a phenomenon that may contribute to the defective antiatherogenic activity of HDL in MetS. PON1 activity did not differ between groups. We conclude that MetS, in addition to the decrease in HDL-C concentration, is associated with alterations in the HDL phenotype, which is comprised of a greater percentage of small HDL subclasses. Furthermore, HDL-LpPLA(2) activity is decreased in MetS patients.

High-Density Lipoprotein Subfractions - What the Clinicians Need to Know

“…Accordingly, average HDL particle size was reduced in women with CAD compared to healthy subjects [13]; patients with acute ischemic stroke had significantly smaller HDL size, more HDL3 and less HDL2b particles [14], and in myocardial infarction survivors, HDL2b was significantly lower than in controls and inversely correlated with body mass index, smoking, TG and low-density lipoprotein-cholesterol (LDL-C) levels [15]. A similar reduction in large HDL2 particles and an increase in small particles were also observed in non-obese type 2 diabetics [16], in overweight and obese subjects [17,18,19], in subjects with metabolic syndrome [20] and in CHD subjects with diabetes when compared to CHD subjects without diabetes [21]. …”

“…In fact, under pathological conditions, including chronic inflammation, oxidative stress, dyslipidaemia, diabetes and atherosclerosis, HDL particles can undergo significant composition and structure modifications thus resulting in ‘dysfunctional HDL', which not only exhibit reduced anti-atherogenic properties, but can also acquire pro-atherogenic characteristics [45]. Subjects with metabolic syndrome show altered anti-atherogenic properties of HDL, due to changes in the activity of HDL-associated enzymes [20]; HDL3 from type 2 diabetics display a significantly reduced anti-oxidant activity, due to altered composition of this subfraction linked to oxidative stress, glycaemia and hypertrygliceridemia [46]. Both HDL2 and HDL3 from familial hypercholesterolemic (FH) subjects display a reduced ability to mediate cholesterol efflux compared to lipoproteins from normolipidemic subjects [47].…”

The Human Paraoxonase Gene Cluster As a Target in the Treatment of Atherosclerosis

“…An investigation of the relationship between adiponectin and PON1 showed that PON1 activity correlated positively with HDL-C and adiponectin levels and negatively with body-mass index, waist circumference, systolic blood pressure, levels of HbA(1C), insulin, homeostatic model assessment-insulin resistance, and other markers of metabolic syndrome (29). Some studies, however, have failed to find a positive relationship between metabolic syndrome and serum PON activity (184,327). In leptin-and LDL receptor-deficient mice, which serve as a model for metabolic syndrome, adenoviral overexpression of human PON1 significantly reduced the total plaque volume, the plaque macrophage volume, and plaque-associated oxLDL.…”

Modulation of Macrophage Fatty Acid Content and Composition by Exposure to Dyslipidemic Serum in Vitro

“…Our results link dyslipidemia with altered macrophage phenotype favouring foam cell formation. However, further investigation is needed to clarify whether increased TG or reduced HDL is the primary factor underlying this association, and to clarify whether qualitative rather than quantitative alterations in LDL or HDL might play a role in this context [37].…”