Small, Dense Low-Density Lipoprotein-Cholesterol and Atherosclerosis: Relationship and Therapeutic Strategies

Abstract

Low-density lipoprotein cholesterol (LDL-C) plays an important role in the formation, incidence, and development of atherosclerosis (AS). Low-density lipoproteins can be divided into two categories: large and light LDL-C and small, dense low-density lipoprotein cholesterol (sdLDL-C). In recent years, an increasing number of studies have shown that sdLDL-C has a strong ability to cause AS because of its unique characteristics, such as having small-sized particles and low density. Therefore, this has become the focus of further research. However, the specific mechanisms regarding the involvement of sdLDL-C in AS have not been fully explained. This paper reviews the possible mechanisms of sdLDL-C in AS by reviewing relevant literature in recent years. It was found that sdLDL-C can increase the atherogenic effect by regulating the activity of gene networks, monocytes, and enzymes. This article also reviews the research progress on the effects of sdLDL-C on endothelial function, lipid metabolism, and inflammation; it also discusses its intervention effect. Diet, exercise, and other non-drug interventions can improve sdLDL-C levels. Further, drug interventions such as statins, fibrates, ezetimibe, and niacin have also been found to improve sdLDL-C levels.

Keywords: atherosclerosis; endothelial injury; inflammation; lipid metabolism; review; small dense low-density lipoprotein-cholesterol.

Figure 1

Classification of lipoprotein cholesterol. Lipoprotein with density <0.95 g/ml, diameter of 80–500 nm is chylomicrons, density of 0.95–1.006 g/ml, diameter of 25–80 nm is very low density lipoprotein, density of 1.063–1.21 g/ml, diameter of 8–15 nm is high density lipoprotein, density of 1.006–1.063 g/ml, diameter of 18–28 nm is low density lipoprotein, Among them, low-density lipoprotein is divided into seven subtypes. The third to seventh subtypes are small and dense low-density lipoprotein with density >1,004 g/ml and diameter <25.5 nm.

Figure 2

Mechanisms of atherosclerosis induced by sdLDL-C. (A) Lipid metabolism: SdLDL-C reduces the expression of ATF3 and EGR2, ATF3 decreases the ability of SR-BI by interacting with p53 and 4α and promotes CYP8B1 to inhibit cholesterol reverse transport; EGR2 leads to an increase in CE production and FC outflow, thus increasing the oxidation sensitivity of sdLDL-C. On the other hand, the low affinity of apoB-100 on the surface of LDL-C receptors and sdLDL-C makes it difficult for the receptors to recognize sdLDL-C and is more easily absorbed by phagocytes to form foam cells and promote the occurrence and development of AS. (B) Oxidative stress: The increase of sdLDL-C level reduces the production of VLCFA and miR-126, which affects lipid metabolism and fatty acid β oxidation; miR-126 affects HDL uptake, and enhances signal transduction resulting in AS. In addition, ox-sdLDL can also increase the expression of adhesion molecules and induce excessive production of ROS and RNS, resulting in the enhancement of oxidative stress to cause AS. (C) Fibrinolytic system: SdLDL-C increases the levels of PAI-1 and TXA2. PAI-1 inhibits the function of u-PA and t-PA, which easily leads to thrombosis. TXA2 activates TP receptor and activates RhoA/Rho21 kinase pathway through its G protein coupled receptor, and increases calcium levels in hepatic stellate cells, resulting in vasoconstriction, platelet aggregation, thrombosis and AS. (D) Inflammation: SdLDL-C levels reduces IDO, causing a decrease in vascular tolerance by affecting the Kyn pathway; LP-PLA2 increased that activated TRPC1/TRPC3 channels, calcium influx, Bax and caspase-3 pathways to cause apoptosis; increased expression of inflammatory cytokines and the formation of foam cell, suggesting an inflammatory response. SdLDL-C, small, dense low-density lipoprotein cholesterol; AS, atherosclerosis; CE, cholesterol ester; FC, free cholesterol; VLCFA, very-long-chain fatty acid; ATF3, activating transcription factor 3; LDs, lipid droplets; IDO, indoleamine 2,3-dioxygenase; LP-PLA2, lipoprotein-associated phospholipase A2; LPCs, lysophosphatidylcholine; ROS, reactive oxygen species; RNS, reactive nitrogen species; PAI-1, plasminogen activator inhibitor 1; TXA2, thromboxane A2; t-PA, tissue type plasminogen activator; u-PA, urokinase type plasminogen activator.