Lipoprotein Subfractionation: VLDL Size (NMR)

Optimal Takeaways  

Very low-density lipoprotein (VLDL) is a triglyceride-rich lipoprotein. It undergoes modification in circulation to eventually become LDL as it “drops off” its triglyceride cargo. Larger VLDL particles carry more triglycerides than smaller VLDL particles. Simply measuring total VLDL does not differentiate between large and small particles, and subfraction is needed to assess disease risk best.

Larger VLDL particles are associated with increased risk of cardiovascular disease, insulin resistance, diabetes, pre-diabetes, metabolic-associated fatty liver disease, and low-normal thyroid function. Larger VLDL size may be associated with cardiometabolic risk even if total triglycerides are not elevated.

Standard Range: 41.10 – 61.70 nm

The ODX Range: 0.00 – 47.10 nm

Low or smaller VLDLs are associated with a reduced risk of cardiometabolic disease.

High or larger-sized VLDLs are associated with cardiovascular risk, increased coronary artery calcium, atheroma, (Colhoun 2002), high carbohydrate intake, type 2 diabetes, (German 2006), prediabetes (de Carvalho 2022), metabolic syndrome, decreased adiponectin (Lucero 2012), low-normal thyroid function (van Tienhoven-Wind 2015), excess fatty acids and glucose, insulin resistance (Ginsberg 2021), higher serum triglycerides, higher VLDL particle number, and smaller LDLs (Sokooti 2021).

Overview    

Very low-density lipoproteins (VLDL) are the main transporters of triglycerides in the blood though they also carry approximately 10-15% of the cholesterol in circulation (Raymond 2021). If that percentage exceeds 25%, the risk of coronary artery disease will also increase. The apoB component of VLDL makes cholesterol more soluble, allowing it to infiltrate the artery wall and increase its atherogenicity (Pagana 2021).

Excess production of larger triglyceride-rich VLDLs can increase the risk of cardiometabolic disorders such as insulin resistance, metabolic syndrome, and type 2 diabetes. This can occur when a surplus of fatty acids, glucose, and liver fat is available. Larger VLDLs are also converted to more atherogenic small dense LDL particles (Adiels 2008).

Triglyceride-rich lipoproteins and their remnants are strongly associated with ischemic stroke, myocardial infarction, and aortic valve stenosis, even in those receiving artificial LDL-lowering therapy with low LDL cholesterol. Accumulation and atherogenicity of VLDL remnants increase as serum triglycerides increase, especially triglycerides above 260 mg/dL (3.0 mmol/L) (Ginsberg 2021). Larger VLDL1 remnants also promote increased triglyceride accumulation in macrophages compared to VLDL2 particles (German 2006).

The size and density of VLDL particles secreted by the liver can vary depending on diet, age, health status, and genetic factors. VLDLs usually range from 30 to 90 nm in diameter, with larger, less dense VLDLs classified as VLDL1 and smaller, denser VLDLs classified as VLDL2 (German 2006). Large VLDL1 particles are approximately 50-80 nm in diameter, while VLDL2 particles are 30-50 nm. The larger VLDL particles observed in insulin resistance are accompanied by atherogenic factors, including higher serum triglycerides, higher VLDL particle number, and smaller LDLs (Sokooti 2021).

One study of 44 subjects found that those with metabolic syndrome had significantly larger VLDLs at 60-90 nm, significantly increased serum free fatty acids, and significantly lower adiponectin. The lower the adiponectin, the more likely large VLDLs will be elevated. Researchers note that increased circulating free fatty acids increased the production of large VLDLs independent of insulin resistance. Also, large VLDLs were elevated in some metabolic syndrome subjects despite normal triglyceride levels (Lucero 2012).

Low-normal thyroid function may contribute to increased triglycerides, VLDL size, and the number of large VLDLs. One study of 113 subjects observed a significant inverse association between free T4 and VLDL size, as well as a number of large VLDLs. Type 2 diabetics in the study had significantly larger VLDL particle size (51.1 nm vs. 44.2 nm) and significantly higher levels of large VLDLs, triglycerides, and small LDLs compared to nondiabetics (van Tienhoven-Wind 2015).

References  

Adiels, Martin et al. “Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome.” Arteriosclerosis, thrombosis, and vascular biology vol. 28,7 (2008): 1225-36. doi:10.1161/ATVBAHA.107.160192

Colhoun, Helen M et al. “Lipoprotein subclasses and particle sizes and their relationship with coronary artery calcification in men and women with and without type 1 diabetes.” Diabetes vol. 51,6 (2002): 1949-56. doi:10.2337/diabetes.51.6.1949

de Carvalho, Luiz Sérgio F., et al. "Biomarkers in Disease: Diabetes Methods, Discoveries, and Applications." Biomarkers in Diabetes. Cham: Springer International Publishing, 2022. 395-409.

German, J Bruce et al. “Lipoproteins: When size really matters.” Current opinion in colloid & interface science vol. 11,2-3 (2006): 171-183. doi:10.1016/j.cocis.2005.11.006

Ginsberg, Henry N et al. “Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society.” European heart journal vol. 42,47 (2021): 4791-4806. doi:10.1093/eurheartj/ehab551

Lucero, Diego et al. “Predominance of large VLDL particles in metabolic syndrome, detected by size exclusion liquid chromatography.” Clinical biochemistry vol. 45,4-5 (2012): 293-7. doi:10.1016/j.clinbiochem.2011.12.013

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Sokooti, Sara et al. “Triglyceride-rich lipoprotein and LDL particle subfractions and their association with incident type 2 diabetes: the PREVEND study.” Cardiovascular diabetology vol. 20,1 156. 28 Jul. 2021, doi:10.1186/s12933-021-01348-w

van Tienhoven-Wind, Lynnda, and Robin P F Dullaart. “Low normal thyroid function as a determinant of increased large very low density lipoprotein particles.” Clinical biochemistry vol. 48,7-8 (2015): 489-94. doi:10.1016/j.clinbiochem.2015.01.015