Abstract
Although Lands’ cycle was discovered in 1958, its function and cellular regulation in membrane homeostasis under physiological and pathological conditions remain largely unknown. Nonbiased high throughput metabolomic profiling revealed that Lands’ cycle was impaired leading to significantly elevated erythrocyte membrane lysophosphatidylcholine (LysoPC) content and circulating and erythrocyte arachidonic acid (AA) in mice with sickle cell disease (SCD), a prevalent hemolytic genetic disorder. Correcting imbalanced Lands’ cycle by knockdown of phospholipase 2 (cPLA2) or overexpression of lysophosphatidycholine acyltransferase 1 (LPCAT1), two key enzymes of Lands’ cycle in hematopoietic stem cells, reduced elevated erythrocyte membrane LysoPC content and circulating AA levels and attenuated sickling, inflammation and tissue damage in SCD chimeras. Human translational studies validated SCD mouse findings and further demonstrated that imbalanced Lands’ cycle induced LysoPC production directly promotes sickling in cultured mouse and human SCD erythrocytes. Mechanistically, we revealed that hypoxia-mediated ERK activation underlies imbalanced Lands’ cycle by preferentially inducing the activity of PLA2 but not LPCAT in human and mouse SCD erythrocytes. Overall, our studies have identified a pathological role of imbalanced Lands’ cycle in SCD erythrocytes, novel molecular basis regulating Lands’ cycle and therapeutic opportunities for the disease.
Highlights
Cellular membranes from all of organisms consist of a bipolar lipid bilayer, which contains phospholipids (PLs), cholesterol, and proteins
Overall, nonbiased metabolomic screening revealed that the levels of LysoPLs, especially LysoPC, were most elevated in whole blood but not the plasma, while both plasma and erythrocyte arachidonic acid (AA) levels were increased in Sickle cell disease (SCD) Tg mice (Fig. 1c,d)
Similar to reduction of erythrocyte LysoPC, we found that circulating AA, another product generated by cytosolic PLA2 (cPLA2), was significantly reduced by knockdown of cPLA2 in bone marrow (BM)-derived cells of SCD chimeras (Fig. 3g)
Summary
Cellular membranes from all of organisms consist of a bipolar lipid bilayer, which contains phospholipids (PLs), cholesterol, and proteins. It is well accepted that deoxygenation and polymerization of deoxygenated HbS are initial triggers for sickling, abnormal membrane lipid organization and composition was reported in sickled erythrocytes over three decades ago[4,5,6,7]. Using nonbiased high throughput metabolomic profiling, we found a substantial increase in the concentration of LysoPLs in erythrocytes and AA in the circulation of SCD mice. These findings immediately suggest that Lands’ cycle in SCD erythrocytes is impaired. Extending from metabolomic screening, we conducted both mouse and human studies to systemically address a central question of role and mechanisms of alterations of PLs in SCD with a goal to identify pathogenic alterations in Lands’ cycle in this hemolytic disorder
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