Increased Oxidized High-Density Lipoprotein/High-Density Lipoprotein–Cholesterol Ratio as a Potential Indicator of Disturbed Metabolic Health in Overweight and Obese Individuals

Jelena M. Janac, MPharm; Aleksandra Zeljkovic, PhD; Zorana D. Jelic-Ivanovic, PhD; Vesna S. Dimitrijevic-Sreckovic, PhD; Jelena Vekic, PhD; Milica M. Miljkovic, PhD; Aleksandra Stefanovic, PhD; Jelena M. Kotur-Stevuljevic, PhD; Jasmina M. Ivanisevic, PhD; Vesna V. Spasojevic-Kalimanovska, PhD


Lab Med. 2020;51(1):24-33. 

In This Article

Abstract and Introduction


Background: We evaluated the qualitative characteristics of high-density lipoprotein (HDL) particles in metabolically healthy and unhealthy overweight and obese subjects.

Methods: The study involved 115 subject individuals classified as metabolically healthy and unhealthy, as in overweight and obese groups. Commercial enzyme-linked immunosorbent assay (ELISA) kits were used to measure oxidized HDL (OxHDL) and serum amyloid A (SAA) concentrations. Lipoprotein subfractions were separated using nondenaturing gradient gel electrophoresis.

Results: An independent association was shown between increased OxHDL/HDL-cholesterol ratio and the occurrence of metabolically unhealthy phenotype in the overweight and obese groups. The OxHDL/HDL-cholesterol ratio showed excellent and acceptable diagnostic accuracy in determination of metabolic health phenotypes (overweight group, AUC = 0.881; obese group, AUC = 0.765). Accumulation of smaller HDL particles in metabolically unhealthy subjects was verified by lipoprotein subfraction analysis. SAA concentrations did not differ significantly between phenotypes.

Conclusions: Increased OxHDL/HDL-cholesterol ratio may be a potential indicator of disturbed metabolic health in overweight and obese individuals.


Cardiovascular diseases (CVDs) are leading causes of death worldwide;[1] overweight and obesity are identified as key risk factors.[2] Besides the established independent relationship with increased CVD morbidity and mortality, overweight and obesity are associated with the development of dyslipidemia, hypertension, and glucose intolerance.[2] Nevertheless, it is recognized that subject individuals with excess body weight are not homogenous in terms of degree of metabolic disturbances.[3]

Although a unique definition has still not adopted, 2 distinct phenotypes are recognized among overweight and obese individuals. Numerous studies have demonstrated that overweight and obese subjects with metabolically unhealthy phenotype are characterized by higher levels of intrahepatic triglyceride content and higher carotid intima-media thickness;[4] dysfunctional adipose tissue;[5] less-favorable body-fat distribution;[6] less-advantageous profiles of expressed proteins in visceral adipose tissue and circulating immune cells;[7,8] higher degree of oxidative stress;[9] and higher risk for CVD, diabetes, and mortality,[10] compared with their metabolically healthy counterparts. Nevertheless, mechanisms that would explain the basis of these differences are not fully understood and warrant further investigation.

One of the possible mechanisms that underlie the differences among phenotypes of metabolic health might be related to the alterations of lipoprotein structure and function. Variations in lipoprotein metabolism are crucial steps in atherosclerosis development; determination of lipid profile parameters is required for adequate cardiovascular risk assessment. In that context, the antiatherogenic properties of high-density lipoproteins (HDLs) are traditionally evaluated through levels of HDL-cholesterol, a parameter inversely related to the risk of coronary heart disease (CHD).[11] However, HDL particles are heterogeneous in size, composition, and functional characteristics; such heterogeneity largely depends on individual metabolic status.[12] Accordingly, more-detailed characterization of HDL particles in terms of measurements of HDL heterogeneity is recommended, to obtain more specific information about CHD risk.[13] When evaluating HDL qualitative characteristics, the influence of other factors that impact lipoproteins should be considered. For instance, oxidative stress, which is a hallmark of different pathological conditions, could alter HDL structure and function.[12,14]

Data regarding the relationship between oxidative HDL modification and coronary-artery spasm[15] and an increased risk of CVD events in patients with renal conditions[16] underline the benefits of preserved HDL structure. However, inflammation is another major contributor to alterations of HDL structure.[12] In this context, the impact of serum amyloid A (SAA) on HDL particles should be pointed out. SAA is an inflammatory protein that originates from the liver and adipocytes. It affects HDL structure and metabolism by displacing apolipoprotein AI which altering cholesterol transport, causing decreased HDL affinity for hepatocytes and increased HDL affinity for macrophages,[12,17] thus reflecting the effect of inflammation on HDL particles.

The goal of our study was to evaluate the qualitative characteristics of HDL particles in metabolically healthy and unhealthy overweight and obese subjects. Our research included measurement of OxHDL and SAA concentrations, as well as HDL and low-density lipoprotein (LDL) subfractions analysis. Considering the results of previous reports, we hypothesized that qualitative HDL characteristics would be less favorable in metabolically unhealthy subjects. Also, we explored the discriminative abilities of HDL characteristics in determination of metabolic-health status.