Oral supplementation of an alkylglycerol mix comprising different alkyl chains effectively modulates multiple endogenous plasmalogen species in mice

Paul S, Rasmiena AA, Huynh K, Smith AAT, Mellett NA, Jandeleit-Dahm K, Lancaster GI, Meikle PJ. (2021) Oral supplementation of an alkylglycerol mix comprising different alkyl chains effectively modulates multiple endogenous plasmalogen species in mice. Metabolites

Plasmalogens are a class of lipids that contain a vinyl-ether bond at sn-1. The double bond causes this lipid class to have a more compact structure and leads to important roles in membrane structure, membrane fusion, cholesterol transport, and anti-oxidant properties through scavenging radical oxygen species. Plasmalogens are found in most mammalian tissues, and are most abundant in the brain, heart, kidney, skeletal muscle, and in some immune cells. Due to their variety of roles and distribution throughout the body, it is unsurprising that when plasmalogen levels are reduced it is associated with diseases including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and rhizomelic chondrodysplasia punctata. Prior work looking at plasmalogen precursors as suitable plasmalogen replacement therapies have demonstrated some incorporation of plasmalogens, but generally do not reproduce the normal plasmalogen distribution pattern. As batyl (O-18:0), chimyl (O-16:0), and selachyl (O-18:1) alcohols individually only increase plasmalogens with a specific alkyl chain and cause a compensatory decrease in other plasmalogens, Paul et al wanted to investigate the efficacy of a mix of these major alkylglycerols (AKGs) at a 1:1:1 ratio at increasing plasmalogen levels and maintaining the ratios of endogenous plasmalogen species.

To determine whether the AKG mix treatment altered endogenous plasmalogen levels, mice were treated with a daily dose of 12 mg of AKG mix or 10 mg of the vehicle plus 10 mg of vehicle in water by oral gavage for 1, 2, 4, 8, or 12 weeks. In plasma there was an increase in ethanolamine plasmalogens (~5 nmol/μmol to ~9 nmol/μmol) and choline plasmalogens (~2 nmol/μmol to ~4.5 nmol/μmol) over the first two weeks of treatment with these levels being maintained for the rest of the treatment period. In the adipose tissue ethanolamine plasmalogens increased throughout 4 weeks of treatment (~120 nmol/μmol to ~180 nmol/μmol) then were maintained for the rest of the treatment time and the choline plasmalogens only took 2 weeks to double (~5 nmol/μmol to ~10 nmol/μmol) and then were maintained throughout the rest of the study. The liver showed more modest increases in plasmalogens with the ethanolamine plasmalogen showing a significant increase (~11 nmol/μmol to ~13 nmol/μmol) after 12 weeks of treatment and choline plasmalogens increasing after 1 week, but with the greatest difference being at the 12-week timepoint (~2 nmol/μmol to ~3 nmol/μmol). The AKG mix treatment did not improve plasmalogen levels in the skeletal muscle.

To further break down the effects of AKG supplementation across ethanolamine plasmalogen species, species were grouped based on their alkenyl group (PE(P-16:0), PE(P-18:0) and PE(P-18:1)). In plasma it was found that all three groups showed an increase with AKG mix administration, but they did not increase equally. PE(P-18:0) increased the most followed by PE(P-16:0) then PE(P-18:1), but all were statistically significant. In adipose tissue PE(P-18:0) and PE(P-16:0) were significantly increased, but the difference seen in PE(P-18:1) was not significant. In the liver there was only a significant increase in PE(P-18:0) and in skeletal muscle a significant decrease in PE(P-18:1).

Paul et al demonstrated that a mixture of AKG types can provide an increase in total plasmalogens in different tissues and serum, while mostly not causing other plasmalogen species to decrease due to compensatory mechanisms. Previous work investigating supplementation with individual plasmalogen species has demonstrated the ability to increase plasmalogen levels with the same alkenyl chain, but often also causes a reduction in others, as well as some phospholipid species. These findings suggest that plasmalogen levels were able to increase from the AKG mix treatment and that this did not alter the endogenous species present. As well, increases were not seen in all tissues by all three constituents in the AKG mix, and this could be due to more rigid regulation in some tissues, such as skeletal muscle, compared to others. Going forward it would be interesting to see a study directly comparing individual treatments of batyl (O-18:0), chimyl (O-16:0), and selachyl (O-18:1) alcohols to the AKG mix. As well, since the three constituents of the mix did not increase plasmalogen species equally, altering the ratio from 1:1:1 could be useful to optimize the AKG mix treatment.