Plasmalogens Week #5 – Health and Diseases, Part 1

Continuing Plasmalogens Week with three 2025 papers, starting with a human study that included plasmalogen biomarkers of non-communicable disease fatigue symptoms:

“This study explored the biological mechanisms underlying fatigue in patients with NCDs using a multi-omics approach. Our findings indicate that distinct metabolic pathways, salivary microbiota, and genetic factors may contribute to different dimensions of fatigue, including general, physical, and mental fatigue.

General fatigue is associated with unsaturated fatty acid biosynthesis, indicating its role in lipid metabolism.

Physical fatigue was associated with plasmalogen synthesis, mitochondrial beta-oxidation of long-chain fatty acids, and selenoamino acid metabolism, suggesting a potential contribution of impaired energy production.

Mental fatigue is associated with homocysteine degradation and catecholamine biosynthesis, which may influence cognitive fatigue.

This exploratory study suggests that fatigue in patients with NCDs may involve disruptions in lipid metabolism, neurotransmitter pathways, microbial composition, and genetic variations. Blood-based biomarkers showed better predictive potential for physical fatigue, whereas salivary-based models were more indicative of mental fatigue.

Although our findings support the role of lipid metabolism, the contribution of plasmalogen synthesis remains underexplored. Further studies are needed to validate these findings and understand their mechanisms of action.”

https://link.springer.com/article/10.1186/s12911-025-03034-3 “Visualizing fatigue mechanisms in non-communicable diseases: an integrative approach with multi-omics and machine learning”

A human study of metabolic dysfunction-associated steatotic liver disease (MASLD) included investigating plasmalogens:

“In this study, we applied untargeted metabolomic profiling to serum samples from individuals with and without MASLD, classified by the Fatty Liver Index, with the goal of identifying characteristic metabolic signatures and pathways that may underlie disease presence and progression. Individuals in the MASLD group displayed significantly higher levels of ALT, AST, ALP, and GGT, reflecting ongoing hepatic injury, cholestasis, and oxidative stress. However, albumin and bilirubin levels remained within normal limits, indicating early to intermediate disease stages rather than advanced fibrosis or cirrhosis.

A consistent and highly significant lipidomic pattern in the MASLD group is the depletion of plasmalogens and sphingomyelins. Depletion of these lipid classes was identified as a hallmark of insulin resistance as defined by the triglyceride-glucose index. In contrast, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol species were elevated in MASLD, pointing toward broader lipid remodeling events.

Reduced plasmalogen and sphingomyelin levels positions their depletion as a core feature of metabolic dysfunction. Plasmalogens are ether phospholipids with strong antioxidant capacity, and their reduction suggests a loss of protective buffering against oxidative stress, one of the main drivers of MASLD progression. Similarly, sphingomyelin depletion implicates altered membrane dynamics and signaling disturbances, further contributing to metabolic dysfunction.

Depletion of plasmalogens 1-(1-enyl-palmitoyl)-2-oleoyl-GPC (P-16:0/18:1), 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2), 1-(1-enyl-palmitoyl)-2-palmitoyl-GPC (P-16:0/16:0), 1-(1-enyl-palmitoyl)-2-palmitoleoyl-GPC (P-16:0/16:1), 1-(1-enyl-palmitoyl)-2-oleoyl-GPE (P-16:0/18:1), 1-(1-enyl-palmitoyl)-2-linoleoyl-GPE (P-16:0/18:2), and disruption of the glutamate–gamma-glutamyl pathway stand out as central features of metabolic dysfunction in MASLD, with clear potential to inform biomarker discovery, disease classification, and the design of targeted therapeutic strategies.”

https://www.mdpi.com/2218-1989/15/11/687 “Metabolomic Signatures of MASLD Identified by the Fatty Liver Index Reveal Gamma-Glutamyl Cycle Disruption and Lipid Remodeling”

A rodent study investigated dietary sea squirt (AM) plasmalogen ethanolamine (PlsEtn) extract’s and dietary pig liver (PL) phosphatidyl ethanolamine (PtdEtn) extract’s effects on acetaminophen liver injury:

“We investigated dietary effects of PlsEtn from ascidian on chronic hepatic injury in acetaminophen (APAP)-treated mice. Five-week-old male mice were divided into four groups (n = 12), which were treated with experimental diets for two weeks and then the respective APAP-containing diet for five weeks.

Ingested PlsEtn is digested into lysoPlsEtn and free fatty acid in the small intestine. PlsEtn digests are absorbed and are subsequently resynthesized into PlsEtn preferentially with PUFA.

Acetaminophen is a frequently used analgesic and antipyretic. Approximately 90% of APAP is metabolized by UDP-glucuronosyltransferase and sulfotransferase into glucuronic acid and sulfate conjugates, respectively.

5–9% of APAP is metabolized into the highly reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI). This metabolite is considered a pivotal molecule in APAP-induced hepatotoxicity and is conjugated by glutathione (GSH). Excessive NAPQI levels deplete GSH and covalently bind to cellular proteins, resulting in organelle dysfunction, such as mitochondria dysfunction. These impairments induce oxidative stress, cell malfunctions, and subsequently, cell death, such as ferroptosis and apoptosis.

Mice were treated with continuous APAP consumption to induce oxidative stress and impaired lipid metabolism in the liver. Effects of diets were evaluated based on levels of malondialdehyde (MDA), a marker of lipid oxidation, on fatty acid content, and on expression of apoptosis-related proteins in the liver.

The PlsEtn-rich diet effectively suppressed APAP-induced decrease in body and liver weights of mice. However, this suppressive effect was not observed in mice fed a PtdEtn-rich diet. APAP administration decreased the total fatty acid content in the liver, whereas a PlsEtn-rich diet alleviated this decrease and increased the hepatic content of docosahexaenoic acid (DHA).

Owing to the alkenyl linkage, which exhibits antioxidant properties, PlsEtn was expected to markedly suppress hepatic lipid oxidation. However, its suppressive effect was the same extent as that by PtdEtn. Both PlsEtn and PtdEtn contain an ethanolamine base in their structures, and free ethanolamine and its metabolite choline suppress lipid peroxidation. Dietary PlsEtn and PtdEtn may be metabolized into free ethanolamine and its further metabolites, which may alleviate APAP-induced hepatic lipid oxidation.

Dietary ethanolamine glycerophospholipids (EtnGpls) rich in PlsEtn or PtdEtn suppressed APAP-induced lipid oxidation in the liver. Protein expression results revealed that dietary EtnGpls reduced expression of certain apoptosis-related proteins compared to the APAP group. This reduction was more effective in mice fed the PlsEtn-rich diet than in those on the PtdEtn-rich diet.”

https://www.mdpi.com/2076-3417/15/11/5968 “Dietary Ethanolamine Plasmalogen from Ascidian Alleviates Chronic Hepatic Injury in Mice Treated with Continuous Acetaminophen”

This study neither demonstrated nor provided citations for its dietary plasmalogen recycling statements.

Three more plasmalogen health and disease papers are curated in Part 2.