Steady-state haemoglobin level in sickle cell anaemia increases with an increase in erythrocyte membrane n-3 fatty acids
Introduction
Several lines of evidence indicate that clinical disease in patients with sickle cell disease (SCD, HbSS) is not due solely to the point mutation GAG to GTG in the sixth codon of the beta globin gene; rather it is the result of various genetic, cellular, humoral and environmental factors acting in concert [1], [2], [3], [4]. Erythrocyte fluidity, deformability, adhesiveness, blood coagulation [5], [6], [7], [8], [9], and the disruption of normal membrane lipid asymmetry and the consequential shift of reactive pro-aggregatory phosphoglycerides to the outer leaflet of the lipid bilayer are important operative factors in the pathophysiology of SCD.
In normal erythrocytes, membrane phospholipids are distributed asymmetrically between the inner and outer leaflets of the lipid bilayer. The outer leaflet is mainly composed of choline phosphoglycerides (CPG) and sphingomyelin (SPM). The inner leaflet is mostly ethanolamine (EPG) and serine phosphoglycerides (SPG). When red cells sickle, EPG and SPG move from the inner to the outer leaflet, and some CPG shifts to the inner layer [10], [11]. Disruption of normal membrane lipid asymmetry and exposure of the reactive SPG promotes blood coagulation and red cell adherence to other blood cells or vascular endothelium [12], [13], [14], [15]. These processes may facilitate vaso-occlusion and ischaemic organ damage in SCD.
The n-3 and n-6 long-chain polyunsaturated fatty acids (LCPUFA) are vital structural and functional components of cell and sub-cellular membranes. In addition, dihomo-γ- linolenic (DHGLA), arachidonic (AA) and eicosapentaenoic (EPA) acids are the precursors of eicosanoids, potent bio-molecules that regulate cell adhesion, aggregation and inflammation. There is evidence that fluidity, deformability [16], [17], [18] and adhesion [12], [13], [14], [15] of erythrocytes are significantly influenced by alterations of membrane LCPUFA in individuals with and without SCD.
It has been postulated that an imbalance in membrane n-6/n-3 LCPUFA is the antecedent of the loss of membrane asymmetry, blood cell adhesion and aggregation and vaso-occlusion in SCD. In deed, there is evidence that steady-state patients with SCD have abnormal plasma and/or erythrocyte fatty acid composition [19], [20], [21], [22], [23], [24]. However, in most of these studies, either the number of subjects enrolled was small, or only total lipids, total phospholipids or CPG were analysed. Hence, it is not possible to ascertain whether the reported fatty acid abnormalities in patients with SCD affects all the plasma and erythrocyte lipids or it is restricted to a specific plasma or erythrocyte lipid moiety.
The aim of the current study was to investigate, if (a) patients with homozygous SCD disease (HbSS) have abnormal blood fatty acids; (b) the fatty acid abnormalities in erythrocyte and plasma have a similar pattern; (c) there is an association between levels of membrane n-3 and/or n-6 LCPUFA, and the degree of anaemia.
Section snippets
Subjects, materials and methods
Forty-three, 26 male and 17 female, HbSS patients aged 11–43 years (mean±SD; 21±22) were enrolled from the Haematology Clinics, University of Nigeria Teaching Hospital, Enugu, Nigeria. Forty-three, racially matched, healthy HbAA controls, 30 male and 13 female, aged 20–52 years (26±26) were also recruited from individuals visiting the hospital. The patients were in steady state: defined as the absence of sickle cell crisis or acute illness from 1 month before, and up to 2 weeks after blood
Erythrocyte fatty acids
The percent fatty acid composition of erythrocyte phospholipids—CPG, EPG and SPG, and SPM is presented in Table 1, Table 2.
Erythrocyte CPG
Erythrocytes from HbSS patients contained higher proportions of arachidonic (AA, ), adrenic (22:4n-6, ), docosapentaenoic (22:5n-6, DPAn-6, ), α-linolenic (ALA, ) acids and total n-6 metabolites () compared with healthy controls. In contrast, the patients had lower proportions of linoleic (LA, ), eicosapentaenoic (EPA, ),
Discussion
This comprehensive investigation shows that steady-state HbSS patients have abnormal blood fatty acid composition. Although the abnormality was more pronounced in plasma and erythrocyte CPG, it was manifested in all the lipid fractions analysed. This blood lipid perturbation was characterised by higher levels of n-6 fatty acids particularly, adrenic, DPAn-6 and AA, and lower n-3 fatty acids, EPA and total n-3 metabolites, in erythrocyte CPG and EPG. The n-3 fatty acids, EPA, DPA and DHA were
Acknowledgements
This study was supported by the Mother and Child Foundation, Sir Halley Stewart Trust and Thomas H. Smouse Memorial Fellowship Award from the American Oil Chemists’ Society.
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