Research Blog

June 13, 2023

Lipoprotein Subfractionation: Large HDLs (ION)

Optimal Takeaways  

High-density lipoproteins (HDLs) serve several vital functions, including scavenging cholesterol from the periphery and delivering it to the liver for processing or to steroidogenic tissues to produce essential hormones. Larger HDL particles appear to be associated with a reduced risk of cardiovascular disease. Blood concentrations of large HDLs can be influenced by factors such as inflammation, obesity, and menopause and can differ between individuals with type 1 and type 2 diabetes.

Nutrition intervention can increase the concentration of circulating large HDLs, which is considered cardioprotective. Low levels of large HDLs may be associated with an increased risk of cardiometabolic disorders.

Standard Range: 6729.01 – 10000.00 nmol/L  

The ODX Range: 6729.01 – 10000.00 nmol/L                                

Low concentrations of large HDLs are associated with obesity, insulin resistance, metabolic syndrome, type 2 diabetes (Sokooti 2021), and increased uric acid (Vekic 2009).

High concentrations of large HDLs are associated with a lower risk of CVD (El Harchaoui 2009), more significant HDL efflux (Mutharasan 2017), type 1 diabetes (Ahmed 2021), consumption of a specialized nutrition bar (Mietus-Snyder 2012), and eating 1-3 eggs per day (DiMarco 2017).


Cardiovascular risk assessment often includes the evaluation of high-density lipoprotein cholesterol (HDL-C). However, identical HDL-C values between two individuals can be associated with significantly different HDL characteristics and levels of risk. Measuring large HDL particle concentration is superior to measuring HDL-C when evaluating cardiovascular risk.

Research suggests that a higher level of large HDLs is associated with a lower risk of CVD. In one nested case-control study of 2,223 participants from the prospective EPIC-Norfolk Study, those who developed coronary artery disease (fatal or nonfatal)over the 6-year study period had lower levels of large HDLs (El Harchaoui 2009).

The ability of HDL to carry out reverse cholesterol transport (RCT) is a more meaningful indicator of cardiovascular risk than the level of HDL cholesterol. A strong inverse relationship is observed between HDL efflux capacity, a measure of RCT, and atherosclerotic cardiovascular disease risk (Wilkins 2019). The Chicago Healthy Aging Study results indicate that higher concentrations of large HDL particles were associated with greater HDL efflux. Conversely, significantly lower levels of large HDLs were seen in subjects with lipid-rich necrotic core plaque versus those without (Mutharasan 2017).

Evaluation of data from the prospective Malmo Diet and Cancer study revealed that levels of large HDLs, measured by ion mobility subfractionation, were inversely correlated with proatherogenic small and medium-sized LDLs. The pattern of low levels of large HDLs and elevations in small/medium LDLs and triglycerides characterizes the “atherogenic lipoprotein phenotype” (Musunuru 2009).

Lower levels of large HDL particles have been linked to indicators of inflammation, which is a risk factor for cardiovascular and metabolic issues. In a study involving 194 middle-aged individuals without symptoms, smaller and denser HDL particles were associated with higher uric acid levels. Participants with the highest uric acid levels also had elevated fibrinogen and hs-CRP, implying mild inflammation and lipoprotein metabolism changes might increase atherosclerosis risk (Vekic 2009).

Data from the PREVEND study, which included 4,828 participants, indicates that lower levels of large HDL particles may be linked to an increased risk of developing type 2 diabetes, particularly in women. During the 7.3-year follow-up, a decrease in large HDL concentrations was associated with new cases of type 2 diabetes in non-obese individuals. This relationship was not observed in obese participants with a BMI of 30 or higher. Researchers suggest that obesity may negatively impact HDL function and that obesity, insulin resistance, and metabolic syndrome are generally connected to lower concentrations of large HDL particles. (Sokooti 2021). Research also suggests that the menopausal transition period may affect HDL functionality. In one study of 471 women, HDL cholesterol efflux capacity per large HDL particle declined, suggesting that large HDLs became less efficient during this time (El Khoudary 2021).

While a decrease in large HDLs is observed with type 2 diabetes, higher concentrations are observed with type 1 diabetes. One cross-sectional study of 100 type 1 diabetics found that the mean concentration of large HDLs was significantly higher in those with type 1 diabetes versus nondiabetics. Researchers suggest that the increase observed in large HDLs and HDL efflux may be associated with an attempt to mitigate the advance of atherosclerosis in these high-risk individuals (Ahmed 2021).

The concentration of large HDLs was increased by 28% with the twice daily consumption of a high-fiber, fruit-based, nutrient-dense bar containing vitamins and minerals, fruit polyphenolics, non-alkali processed dark chocolate, beta-glucan, whey protein isolate, glutamine, wheat bran, walnuts, and omega-3 DHA for two weeks. Significant increases in glutathione and significant decreases in plasma homocysteine were also observed in the study (Mietus-Snyder 2012)

Interestingly, a study of 38 young, healthy adults found that eating at least 1-3 eggs per day was associated with increased concentrations of large HDL particles. The study also revealed increased blood levels of the antioxidant nutrients lutein and zeaxanthin and increased activity of PON1, an HDL antioxidant enzyme usually associated with smaller HDLs. LDL particle number concentration increased favorably with egg consumption as well, while blood pressure decreased significantly in a dose-dependent manner (DiMarco 2017).

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Ahmed, Mohamad O et al. “HDL particle size is increased and HDL-cholesterol efflux is enhanced in type 1 diabetes: a cross-sectional study.” Diabetologia vol. 64,3 (2021): 656-667. doi:10.1007/s00125-020-05320-3

DiMarco, Diana M et al. “Intake of up to 3 Eggs per Day Is Associated with Changes in HDL Function and Increased Plasma Antioxidants in Healthy, Young Adults.” The Journal of nutrition vol. 147,3 (2017): 323-329. doi:10.3945/jn.116.241877

El Harchaoui, Karim et al. “High-density lipoprotein particle size and concentration and coronary risk.” Annals of internal medicine vol. 150,2 (2009): 84-93. doi:10.7326/0003-4819-150-2-200901200-00006

El Khoudary, Samar R et al. “HDL (High-Density Lipoprotein) Subclasses, Lipid Content, and Function Trajectories Across the Menopause Transition: SWAN-HDL Study.” Arteriosclerosis, thrombosis, and vascular biology vol. 41,2 (2021): 951-961. doi:10.1161/ATVBAHA.120.315355

Mietus-Snyder, Michele L et al. “A nutrient-dense, high-fiber, fruit-based supplement bar increases HDL cholesterol, particularly large HDL, lowers homocysteine, and raises glutathione in a 2-wk trial.” FASEB journal : official publication of the Federation of American Societies for Experimental Biology vol. 26,8 (2012): 3515-27. doi:10.1096/fj.11-201558

Musunuru K, Orho-Melander M, Caulfield MP, et al. Ion mobility analysis of lipoprotein subfractions identifies three independent axes of cardiovascular risk. Arterioscler Thromb Vac Biol. 2009;29:1975-1980.  

Mutharasan, R Kannan et al. “HDL efflux capacity, HDL particle size, and high-risk carotid atherosclerosis in a cohort of asymptomatic older adults: the Chicago Healthy Aging Study.” Journal of lipid research vol. 58,3 (2017): 600-606. doi:10.1194/jlr.P069039

Parra, Eliane Soler et al. “HDL size is more accurate than HDL cholesterol to predict carotid subclinical atherosclerosis in individuals classified as low cardiovascular risk.” PloS one vol. 9,12 e114212. 3 Dec. 2014, doi:10.1371/journal.pone.0114212

Sokooti, Sara et al. “HDL Particle Subspecies and Their Association With Incident Type 2 Diabetes: The PREVEND Study.” The Journal of clinical endocrinology and metabolism vol. 106,6 (2021): 1761-1772. doi:10.1210/clinem/dgab075

Vekic, Jelena et al. “High serum uric acid and low-grade inflammation are associated with smaller LDL and HDL particles.” Atherosclerosis vol. 203,1 (2009): 236-42. doi:10.1016/j.atherosclerosis.2008.05.047          

Wilkins, John T, and Henrique S Seckler. “HDL modification: recent developments and their relevance to atherosclerotic cardiovascular disease.” Current opinion in lipidology vol. 30,1 (2019): 24-29. doi:10.1097/MOL.0000000000000571      


Tag(s): Biomarkers

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