R & D
Background of in vivo & in vitro metabolic fates of phospholipids, ether phospholipids & lysophospholipids

Most of ingested DHA phospholipids (PLs) may pass across intestinal barrier with limited degradation. But a part of the lipids can still be hydrolyzed by pancreatic PLA2 in small intestine to form lysoPLs and DHA. After absorption, it is expected that lysoPLs may be reacylated with released DHA by acyltransferase to reform newly-made DHA PLs that can be combined, along with non-deacylated DHA PLs, with plasma for further deacylation/reacylation cycle in the liver, followed by generating 2-DHA lysoPLs from HDL/2-DHA PLs in the blood-brain barrier. However, the study also reported an alterative but a major pathway of 2-DHA PC synthesis via the PE methylation in rat liver, rather than via acylation lysoPC. A pharmacokinetic study of PS clearly figured out in vivo metabolic fate of the exogenous PS species mixture, which includes: (i) decarboxylation to PE species, and (ii) extensive hydrolytic degradation to other lipids, mainly lysoPE.

The metabolic pathway of ether PLs differs from that of diacyl PLs. Ether PLs are poor substrates for phospholipase A1-like enzymes, but the fatty acids esterified at the sn-2 position of ether PL species can be catalyzed by various PLA2s at very slow rates. This leads to reducing deacylation of DHA ether PL species in absorption and metabolism, and then further combined with HDL in the liver. A study has indicated that brain capillary endothelial cells can bind HDL-3, while a new route by uptake and transport of HDL to the brain with in vitro BBB model has been also reported.

Furthermore, deacylation of the fatty acid from lysophospholipid species, which contain only one acyl fatty acid chain linked to either the sn-1 position or the sn-2 position of the glycerol backbone, is very limited in absorption step. It should be stated here that DHA lysophospholipid species could be ¡°a fastest vehicle¡± in delivery of DHA to the brain. An early in vivo study demonstrated that after intravenous injection of labeled lysoPC-albumin complex to adult squirrel monkeys, exogenous labeled lipids reached in the brain just in 20 minutes. About 70% of injected lysoPC species were taken up in the brain and then acylated to form related PC species, which may be converted to DHA-PS by the PS synthase-1.

Design of the brain DHA transporters based on metabolic fates of phospholipids & ether phospholipids

On the basis of above knowledge on in vivo metabolic pathways of PLs and ether PLs, a serious of ideal brain DHA transporters should be:
The type-1 brain DHA transporters: highly enriched sn-2-DHA - containing molecular species of PLs, which are expected to be not only deacylated easily but also reacylated readily to reform newly-made 2-DHA related PLs in absorption step and general circulation, followed by further releasing 2-DHA lysophospholipid species in the BBB, and then passing across the barrier into the brain;

The type 1 phospholipids-based brain DHA transporters are shown as the following forms of the lipid molecules:

(i) 1-acyl chains/2-DHA phosphatidylethanolamine (PE) species, which can be deacylated easily by pancreatic and other PLA2 and then reacylated readily to reform newly-made 2-DHA PE in general circulation and partial formation of 2-DHA PC in the liver, followed by further releasing endothelial lipase-catalyzed 2-DHA-lysoPC and 2-DHA lysoPE in the BBB;

(ii) 1-acyl chains/2-DHA phosphatidyl-monomethylethanolamine (PMME) species, which can be deacylated easily by pancreatic PLA2 in absorption step and then reacylated readily to reform 2-DHA PMME in general circulation, followed by producing 2-DHA PC through PE methylation in the liver and then further releasing 2-DHA lysoPC in the BBB, and

(iii) 1-acyl chains/2-DHA phosphatidylserine (PS) species, which can be converted into related 2-DHA PE species by decarboxylation in absorption step, and then present in the plasma in form of related 2-DHA PE species, then following the PE metabolic pathways.

The type 2 brain DHA transporters: highly enriched sn-2-DHA - containing molecular species of ether phospholipids, which are expected to be relatively stable and not easy to be deacylated in absorption and metabolism. After that, the lipids can be further combined with HDL for passing toward the BBB, followed by slowly releasing DHA from the 2-DHA ether PLs in the brain.

In vitro and In vivo experiments on the brain DHA transports

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