J Lipid Res. 2014 May;55(5):956-65. doi: 10.1194/jlr.P045591.

Serum choline plasmalogens, particularly those with oleic acid in sn-2, are associated with proatherogenic state.

Nishimukai M, Maeba R, Yamazaki Y, Nezu T, Sakurai T, Takahashi Y, Hui SP, Chiba H, Okazaki T, Hara H.

Division of Applied Bioscience, Research Faculty of Agriculture, Hokkaido University, Sapporo, Hokkaido 060-8589, Japan.

 

Abstract

Serum plasmalogens (Pls) (1-O-alk-1′-enyl-2-acyl glycerophospholipids) are of particular interest for studies on metabolic disorders associated with oxidative stress and chronic inflammation. Serum levels of Pls are known to correlate positively with HDL-cholesterol (HDL-C); however, few studies have examined serum Pls molecular species in association with pathophysiological conditions and their clinical significance. To clarify these, we determined serum levels of individual ether glycerophospholipids in Japanese asymptomatic cohorts (n = 428; 362 male and 66 female subjects) by LC/MS/MS, and examined their correlations with clinical parameters. We found that the proportion of choline Pls (PlsCho) among total serum phospholipids was significantly lower in the male group over 40 years old and was associated with multiple risk parameters more strongly than HDL-C. The abundance of serum PlsCho with oleic acid (18:1) in sn-2 exhibited the strongest positive correlation with serum concentrations of adiponectin and HDL-C, while being inversely associated with waist circumference and the serum levels of TG and small dense LDL-cholesterol. The characterization of serum ether glycerophospholipids verified the specificity of PlsCho, particularly the ones with 18:1 in sn-2, as a sensitive biomarker for the atherogenic state.

KEYWORDS: atherosclerosis; ether glycerophospholipid; high density lipoprotein-cholesterol; serum biomarker

PMID: 24616482

 

Supplements:

Emerging pathological evidences indicate that oxidative stress and chronic inflammation are involved in major age-related diseases such as atherosclerosis, dementia, and cardiovascular diseases. Peroxisomes dysfunction may be related to aging and age-related pathologies, possibly through the derangement of redox homeostasis. Peroxisomes are essential organelles in higher eukaryotes for redox homeostasis, as well as a large number of metabolic functions. In addition, cumulative evidences suggest that peroxisomes function as potential regulators of oxidative stress-related signaling pathways. These notions suggest that peroxisome dysfunction is not only associated with rare peroxisomal disorders, but also with more common age-related diseases related to oxidative stress.

The biosyntheses of plasmalogens (Pls), a subclass of glycerophospholipids, are primarily regulated by peroxisomes. Thus, Pls levels may reflect the functional activity of peroxisomes, and serve as a potential biomarker for diseases related to oxidative stress and aging. Pls are characterized by the presence of a vinyl-ether bond at the sn-1 position of the glycerol backbone. On the basis of their polar head groups at the sn-3 position, Pls are mainly classified into either choline plasmalogens (PlsCho) or ethanolamine plasmalogens (PlsEtn); the former are localized in a few tissues such as cardiac muscle and blood plasma, whereas the latter belong to a predominant class distributed in a wide variety of cells and tissues. Human plasma/serum Pls are synthesized in and secreted from liver, intestine, and kidney to circulating blood as lipoprotein components, and distributed almost equally through all lipoprotein fractions. The concentration of plasma/serum Pls is 100-300 μM with PlsCho/PlsEtn ratio in the range of 0.5-1.5.

Pathophysiological roles of Pls are poorly understood. Some patients with peroxisomal disorders exhibit the systemic reduction of Pls and various pathological conditions, such as severe mental retardation, hypotonicity, adrenal dysfunction, cataracts, deafness, facial dysmorphism, chondrodysplasia, and a failure to thrive. Plasmalogen biosynthesis knock out mouse also exhibit similar phenotypes, particularly central nervous system dysfunction. As PlsEtn are abundant in the brain and play essential roles in neuronal functions and myelin formation, defects in PlsEtn contents represent a pathological factor for a number of neurodegenerative disorders such as Alzheimer’s disease (AD). Goodenowe et al. reported that the serum level of PlsEtn containing docosahexaenoic acid (DHA; 22:6) could be a useful biomarker for the early detection and long-term follow-up of AD. In addition, Pls are suggested to modulate membranes properties involved in the formation of non-bilayer structures, or facilitation of membrane fusion. These characteristic features of Pls in modulating biomembranes may be involved in the manifestation of diverse pathophysiological conditions.

Recently, particular attention has been paid to the involvement of Pls in metabolic diseases associated with oxidative stress and chronic inflammation. Studies have postulated that Pls serve as endogenous antioxidants and protect membrane lipids and lipoprotein particles from excessive oxidation by scavenging reactive oxygen species via the vinyl-ether moiety. In addition, Pls function as reservoirs for precursor fatty acids, such as arachidonic acid and DHA, which generate bioactive lipid mediators related to inflammation.

The present paper provides the reference data from 428 Japanese asymptomatic subjects on their serum levels of individual ether glycerophospholipid species. By analyzing the correlation of each molecular species with clinical parameters or biochemical measurements, we found that PlsCho, particularly those containing oleic acid (18:1) in the sn-2 position, were strongly associated with a wide range of risk factors for metabolic syndrome/atherosclerosis. This finding was supported by the global analysis of serum ether glycerophospholipids molecular profiles of coronary artery disease (CAD) patients [1]. In this study, we found that the serum concentrations of PlsCho were not only significantly lower in males with significant coronary stenosis but also associated with atherosclerosis-related parameters, and that serum PlsCho containing 18:1 or linoleic acid (18:2) in sn-2 showed the highest correlations with a wide range of atherogenic parameters among PlsCho molecular species. These results indicate that serum PlsCho, particularly those containing 18:1 in sn-2, may serve as reliable biomarkers for atherosclerosis.

RM FIG1

Serum levels of Pls correlate positively and strongly with high-density lipoprotein cholesterol (HDL-C) concentration (Fig.1). This highly positive relationship suggests that plasma Pls may be involved in HDL metabolism and/or functions. Recent lipidomic analysis demonstrated that individuals with low HDL-C displayed changes in the quality of HDL particles, along with decreased Pls contents. HDL particles exert anti-atherogenic effects through various aspects, such as anti-oxidant, anti-inflammation, and cholesterol efflux from macrophage. Interestingly, Pls-deficient cells have been shown to exhibit reduced cholesterol efflux by HDL, which may be associated with impaired cellular processing of cholesterol. In addition, phospholipids in HDL particles have been suggested to play important roles in HDL-mediated reverse cholesterol transport. We have found that Pls contents in HDL particles significantly associate with the capability of HDL to efflux cholesterol (unpublished data). Anti-oxidative and anti-inflammatory effects are common features in both HDL and Pls. These notions suggest the relevance of plasma Pls to the physiologically important functions of HDL (Fig.2). Recent epidemiologic studies suggest that the quality of HDL including cholesterol efflux ability is more useful indicator for preventing CAD than the quantity of HDL particles. Serum levels of Pls may become an alternative biomarker for the quality of HDL (Fig.3).

RM FIG2

We have established the three promising analytical methods to determine plasma/serum Pls levels, viz. high performance liquid chromatography with radioactive iodine, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and enzymatic assay [2]. Among the established methods, LC-MS/MS is a powerful tool for analyzing the molecular species of Pls that enables us to obtain detailed information regarding plasma/serum Pls. However, the instrumental analyses are too labor intensive and time consuming to be useful for routine work. On the other hand, enzymatic assay is a quick and facile method, which enables its widespread use.

RM FIG3
References

[1] M. Nishimukai, R. Maeba, A. Ikuta, N. Asakawa, K. Kamiya, S. Yamada, et al., Serum choline plasmalogens-those with oleic acid in sn-2-are biomarkers for coronary artery disease, Clin. Chim. Acta. 437C (2014) 147–154.

[2] R. Maeba, M. Nishimukai, S. Sakasegawa, D. Sugimori, H Hara., Plasma/serum plasmalogens: methods of analysis and clinical significance, Advances in Clinical Chemistry 70 (2015, in press).

 

 

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