Plasma Levels of Acyl-Carnitines and Carboxylic Acids Correlate With Cardiovascular and Kidney Function in Subjects With Sickle Cell Trait

Abstract

Subjects with sickle cell trait (SCT) carry one copy of mutated β-globin gene at position E6V at the origin of the production of sickle hemoglobin (HbS). Indeed, individuals with SCT have both normal hemoglobin and HbS, in contrast to patients with sickle cell disease who inherited of two copies of the mutated gene. Although SCT is generally benign/asymptomatic, carriers may develop certain adverse outcomes such as renal complications, venous thromboembolism, exercise-induced rhabdomyolysis … However, little is known about whether similar metabolic pathways are affected in individuals with SCT and whether these metabolic derangements, if present, correlate to clinically relevant parameters. In this study, we performed metabolomics analysis of plasma from individuals with sickle cell trait (n = 34) compared to healthy controls (n = 30). Results indicated a significant increase in basal circulating levels of hemolysis markers, mono- (pyruvate, lactate), di- and tri-carboxylates (including all Krebs cycle intermediates), suggestive of systems-wide mitochondrial dysfunction in individuals with SCT. Elevated levels of kynurenines and indoles were observed in SCT samples, along with increases in the levels of oxidative stress markers (advanced glycation and protein-oxidation end-products, malondialdehyde, oxylipins, eicosanoids). Increases in circulating levels of acyl-carnitines and fatty acids were observed, consistent with increased membrane lipid damage in individuals with sickle cell trait. Finally, correlation analyses to clinical co-variates showed that alterations in the aforementioned pathways strongly correlated with clinical measurements of blood viscosity, renal (glomerular filtration rate, microalbuminuria, uremia) and cardiovascular function (carotid-femoral pulse wave velocity, blood pressure).

Metabolic signatures of cardiorenal dysfunction in plasma from sickle cell patients, as a function of therapeutic transfusion and hydroxyurea treatment

“…Of note, elevated kynurenine levels had been previously associated with increased susceptibility to hemolysis in the context of obesity, 62 whereby depletion in circulating free fatty acids (previously also reported in pediatric patients with SCD 63 ) and elevation acyl-carnitines had been identified as a marker of increased membrane RBC lipid damage and remodeling. This observation was in keeping with previous reports on the activation of the so-called Lands cycle in the context of SCD 64 (or even just sickle cell trait) 65 , or other osmotic, mechanical or oxidative stressors to RBCs, such as blood storage, 66 exercise, 67 chronic 68 or acute kidney dysfunction. 69 Of note, our findings expand on these observations, by identifying acyl-carnitine accumulation (and correction thereof by transfusion more than hydroxyurea treatment) as a hallmark of cardiorenal dysfunction in the sickle cell patient population.…”

Red Blood Cell Metabolism In Vivo and In Vitro

“…The acyl-coA/acyl-carnitine system can then fuel the transfer of new fatty acids to the lysophospholipid, restoring phospholipid composition. Carnitine availability limits the rate of this pathway, known as the Lands cycle, which is activated in response to oxidant stress (e.g., in response to exercise [ 109 ] or in patients with hemoglobinopathies, such as sickle cell trait [ 110 ] and sickle cell disease [ 111 , 112 ]).…”

Complete absence of GLUT1 does not impair human terminal erythroid differentiation

“…Finally, and most evidently, L-carnitine and all acyl-carnitines (AC) were found to increase in the KO reticulocytes (Figure 5A). In mature RBCs this class of metabolites is associated with lipid membrane damage repair via the Lands cycle 34 , represented in Figure 5B. Lipidomics results indicated significant decreases in the levels of cholesteryl-esters (ChE), diacylglycerols (DG), ceramides (Cer) and all phospholipids (PC, PE, PI, PS, PG, PA) in the KO group, except for triacylglycerols (TG), free fatty acids (FFA), and mono-hexosylceramides (Hex1Cer) – Supplemental figure S7 .…”