Phospholipid and fatty acid specificity of endothelial lipase: Potential role of the enzyme in the delivery of docosahexaenoic acid (DHA) to tissues

Abstract

Docosahexaenoic acid (DHA; 22:6 n-3) is an essential fatty acid required for the normal function of several tissues, especially the brain. Previous studies suggested that lysophosphatidylcholine (lysoPC) is a preferred carrier of DHA to the brain, although the pathways of the formation of DHA-containing lysophospholipids in plasma have not been delineated. We propose that endothelial lipase (EL), a phospholipase A1 that plays an important role in the metabolism of high density lipoproteins, may be responsible for the generation of DHA lysophospholipids in plasma. Here we studied the substrate specificity of EL using deuterium-labeled phospholipids with different polar head groups, as well as DHA-enriched natural phospholipids to test this hypothesis. Glycerol-stabilized phospholipids were treated with recombinant EL, and the products were analyzed by liquid chromatography/electrospray ionization mass spectrometry. EL showed the polar head group specificity in the order of phosphatidylethanolamine>phosphatidylcholine>phosphatidylserine>phosphatidic acid. Within the same phospholipid class, the enzyme showed preference for the species containing DHA at the sn-2 position, and was inactive in the hydrolysis of phospholipids containing an ether linkage. Since EL is known to be secreted by the cells of blood-brain barrier, we suggest that it plays an important role in the delivery of DHA lysophospholipid carriers to the brain.

RETRACTED ARTICLE: Aging decreases rate of docosahexaenoic acid synthesis-secretion from circulating unesterified α-linolenic acid by rat liver

“…Newly synthesized DHA in liver is secreted into the plasma in triglyceride and phospholipid-rich lipoproteins, which can undergo lipolysis by a DHA-selective endothelial lipase (Chen and Subbaiah 2007). The resulting unesterified DHA can enter the brain to replace DHA lost due to metabolism (DeMar et al 2004).…”

Lysophosphatidylcholine Pretreatment Reduces VLA-4 and P-Selectin–Mediated B16.F10 Melanoma Cell Adhesion In vitro and Inhibits Metastasis-Like Lung Invasion In vivo

“…Such an exposure of tumor cells to LysoPC levels above a threshold concentration might also occur when empty liposomes are applied, as in the AsPC1 pancreatic cancer model (8). We postulate that a locally increased intratumoral LysoPC concentration might be a consequence of enzymatic hydrolysis of liposomal PLs (12)(13)(14)(15), such as by PLA2-active tumor cells themselves, accumulated passively in the tumor tissue due to the enhanced permeability and retention effect (24).…”

“…We postulated an enzymatic hydrolysis of accumulated liposomes similar to PL in lipoproteins (12)(13)(14)(15), such as by PLA2-active tumor cells. The resulting high intratumoral concentrations of LysoPC containing saturated FA might be responsible for the observed effects.…”

“…14, 15). These enzymes mostly hydrolyze lipoprotein-associated PL, both at the SN À1 as well as the SN À2 position (11)(12)(13)(14)(15)(16), thereby contributing to a pool of LysoPL that represents about one tenth of the total amount of plasma PL (9). The concentration of LysoPC was found to be constant in blood plasma of healthy persons, ranging from 200 to 300 mmol/L (16) or 300 to 400 mmol/L (17,18), suggesting a sensitive balance between generation and removal of LysoPC (e.g., by cellular uptake).…”

Administration of DHA-PS to Aged Mice Was Suitable for Increasing Hippocampal PS and DHA Ratio

“…However, the authors did not examine the mechanisms of PS incorporation into the hippocampus. The pathway of PS incorporation into the hippocampus is thought to be as follows: (i) PS may be incorporated into the brain through the blood-brain barrier (BBB) as LysoPS 39) ; and (ii) PS was hydrolyzed to supply free serine, which is a substrate of base-exchange enzymes in the brain.…”