Featured Article: Depletion of HDL₃high density lipoprotein and altered functionality of HDL₂in blood from sickle cell patients

Abstract

In sickle cell disease (SCD), alterations of cholesterol metabolism is in part related to abnormal levels and activity of plasma proteins such as lecithin cholesterol acyltransferase (LCAT), and apolipoprotein A-I (ApoA-I). In addition, the size distribution of ApoA-I high density lipoproteins (HDL) differs from normal blood. The ratio of the amount of HDL2 particle relative to the smaller higher density pre-β HDL (HDL3) particle was shifted toward HDL2. This lipoprotein imbalance is exacerbated during acute vaso-occlusive episodes (VOE) as the relative levels of HDL3 decrease. HDL3 deficiency in SCD plasma was found to relate to a slower ApoA-I exchange rate, which suggests an impaired ABCA1-mediated cholesterol efflux in SCD. HDL2 isolated from SCD plasma displayed an antioxidant capacity normally associated with HDL3, providing evidence for a change in function of HDL2 in SCD as compared to HDL2 in normal plasma. Although SCD plasma is depleted in HDL3, this altered capacity of HDL2 could account for the lack of difference in pro-inflammatory HDL levels in SCD as compared to normal. Exposure of human umbilical vein endothelial cells to HDL2 isolated from SCD plasma resulted in higher mRNA levels of the acute phase protein long pentraxin 3 (PTX3) as compared to incubation with HDL2 from control plasma. Addition of the heme-scavenger hemopexin protein prevented increased expression of PTX3 in sickle HDL2-treated cells. These findings suggest that ApoA-I lipoprotein composition and functions are altered in SCD plasma, and that whole blood transfusion may be considered as a blood replacement therapy in SCD. Impact statement Our study adds to the growing evidence that the dysfunctional red blood cell (RBC) in sickle cell disease (SCD) affects the plasma environment, which contributes significantly in the vasculopathy that defines the disease. Remodeling of anti-inflammatory high density lipoprotein (HDL) to pro-inflammatory entities can occur during the acute phase response. SCD plasma is depleted of the pre-β particle (HDL3), which is essential for stimulation of reverse cholesterol from macrophages, and the function of the larger HDL2 particle is altered. These dysfunctions are exacerbated during vaso-occlusive episodes. Interaction of lipoproteins with endothelium increases formation of inflammatory mediators, a process counteracted by the heme-scavenger hemopexin. This links hemolysis to lipoprotein-mediated inflammation in SCD, and hemopexin treatment could be considered. The use of RBC concentrates in transfusion therapy of SCD patients underestimates the importance of the dysfunctional plasma compartment, and transfusion of whole blood or plasma may be warranted.

Altered HDL particle in sickle cell disease: decreased cholesterol content is associated with hemolysis, whereas decreased Apolipoprotein A1 is linked to inflammation

“…The authors suggested that this was associated with the structural and functional changes seen in the HDL 2 and HDL 3 particles in SCD. As the level of HDL 3 is lowered in SCD, the Apo A1 exchange rate also decreases; thus affecting cholesterol import and export by the HDL particle, which is worsened by the fact that there is an overall reduction in HDL-C levels in patients with SCD [36]. Sexias et al previously suggested that SCD patients with low HDL and relatively increased TG might have a specific dyslipidemic phenotype of the disease [5].…”

Cardiovascular Risk Assessment in Children With Chronic Cholestatic Liver Diseases

“…Hypercholesterolemia and Lp-X formation associated with obstructive cholestasis are correlated with an increase in hepatic cholesterol synthesis and are independent of plasma HDL. LCAT is expressed and secreted primarily by the liver and functions in the plasma compartment to catalyze the fatty acid esterification of free cholesterol to form cholesteryl esters, a process important for the maturation of HDL as well as the interconversion of APO B-containing lipoproteins (40,41). All recruited children had normal or low BMI-SDS and Waist-SDS and they did not present with features of metabolic syndrome, thus impact of other external cardiovascular risk factors was diminished.…”

Acacia Senegal (Gum Arabic) Supplementation Modulate Lipid Profile and Ameliorated Dyslipidemia among Sickle Cell Anemia Patients

“…A point mutation in the beta globin gene results in a dysfunctional red blood cell and leads to the vasculopathy that defines SCD [25]. In SCD patients, cholesterol metabolism appears dysfunctional, as evidenced by abnormal plasma cholesterol, TG, and fatty acid content, in addition to low HDL [25, 26]. To date, there is no well-established consensus among providers on the management of the complications of SCD [27].…”