Review
Plasmalogens the neglected regulatory and scavenging lipid species

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Abstract

Plasmalogens are a class of phospholipids carrying a vinyl ether bond in sn-1 and an ester bond in sn-2 position of the glycerol backbone. Although they are widespread in all tissues and represent up to 18% of the total phospholipid mass in humans, their physiological function is still poorly understood. The aim of this review is to give an overview over the current knowledge in plasmalogen biology and pathology with an emphasis on neglected aspects of their involvement in neurological and metabolic diseases. Furthermore a better understanding of plasmalogen biology in health and disease could also lead to the development of better diagnostic and prognostic biomarkers for vascular and metabolic diseases such as obesity and diabetes mellitus, inflammation, neuro-degeneration and cancer.

Highlights

• Plasmalogens are phospholipids, characterized by a vinyl ether bond in sn1 position. • Physiological membrane components, anti-oxidants, reservoir for second messengers. • Pathophysiological involvement in neurological and metabolic diseases. • Candidate biomarkers in plasma, blood cells and lipoproteins. • Promising future use for disease detection and monitoring.

Introduction

Plasmalogens represent a class of phospholipids characterized by a vinyl ether bond in sn-1 and an ester bond in sn-2 position of the glycerol backbone. They are expressed in numerous mammalian tissues at varying amounts and exhibit a distinct species distribution. The predominant classes of plasmalogens are glycerophosphoryl-ethanolamine (PE) and glycerophosphoryl-choline (PC), depending on the head-group. The basic chemical structure common to all plasmalogens is depicted in Fig. 1A. The long chain fatty alcohol (R1) in sn-1 consists almost exclusively of 16:0, 18:0, and 18:1 alkenyl groups, while sn-2 (R2) is esterified predominantly with ω-6 or ω-3 derived polyunsaturated fatty acids (Nagan and Zoeller, 2001). While the sn-2 acyl chain is at all segments oriented perpendicularly to the membrane surface, the headgroup lacks a carbonyl oxygen in sn-1 position and therefore exhibits a stronger lipophilicity. This change in headgroup structure in turn leads to stronger intermolecular hydrogen bonding between head groups (Lohner, 1996) and is able to directly disturb cellular membranes (Jaffe and Gottfried, 1968). Although plasmalogens constitute 18% of the total phospholipid mass in humans (Nagan and Zoeller, 2001), for quite some time they have been considered an oddity with no clearly ascribable physiological function aside from being a membrane structure component. Till now an increasing number of cellular functions have been uncovered, including neurochemical effects, intra- and extra-cellular signaling, and the ability to act as radical scavengers. There have also been reports on their involvement in the proper assembly and function of multispan transmembrane transport proteins and ion-channels (Hashimoto et al., 2005) and on the diffusion of NO and other signal-transduction molecules (Guo et al., 2008). Pathophysiologically they seem not only to be involved in neurodegeneration, which was the first disease-association discovered, but also play a role in common diseases such as cardiac failure, type 2 diabetes, obesity, inflammation, and cancer. Further possibilities to address plasmalogen biology in vivo were finally opened up in 2006 when an ether-lipid deficient mouse model was generated (Gorgas et al., 2006).

The aim of this review is to summarize the current knowledge in plasmalogen biology and to address neglected aspects of their role in health and disease.

Section snippets

Biosynthetic pathway

Plasmalogens are characterized by a short half-life, about 30 min for PC plasmalogens and 3 h for PE plasmalogens (Rintala et al., 1999). Therefore their amount in the cellular membrane can rapidly adapt to changing environmental conditions.

Biosynthesis of plasmalogens involves two major cellular compartments: peroxisomes and the endoplasmic reticulum (ER). An overview over the synthetic pathway is depicted in Fig. 1B. The first two steps of plasmalogen biosynthesis take place exclusively in

Plasmalogens as membrane components

Depending on the tissue, plasmalogens constitute a varying but significant amount of total membrane lipids, e.g., in the brain they account for 30–50% of total PE species (Nagan and Zoeller, 2001). The importance of plasmalogens in cellular membranes has been extensively studied in plasmalogen deficient cells. These cells exhibit decreased transmembrane protein function (Perichon et al., 1998) and decreased membrane-related intracellular (Munn et al., 2003) and extra cellular (Mandel et al.,

Role of plasmalogens in neurological diseases

Since plasmalogens are highly expressed in the nervous system and play an important role in many cellular functions in neurons, defects in plasmalogen synthesis represent a pathophysiological factor in a multitude of neurological disorders. Although the following sections try to provide an overview over the most common plasmalogen related diseases this compilation is not exhaustive.

Plasmalogens in metabolic and inflammatory disorders

Recently, in addition to their role in neurological diseases, insights were provided for the involvement of plasmalogens in metabolic diseases and under inflammatory conditions. In these cases changes in plasmalogen levels can either represent the cause of the problem or merely appear as a consequence of metabolic changes. This seems to be of special importance with the emerging field of immunometabolism, linking immunological alterations to metabolic diseases like diabetes and obesity (Mathis

Plasmalogens as candidate biomarkers in blood samples

The blood cell compartment can be regarded as a liquid organ, which is easily accessible for biochemical analysis. This opens up the possibility to identify new functional biomarkers for the detection and follow-up of diseases. Blood samples can be analytically subdivided into three distinct entities: plasma, lipoproteins and blood cells.

Concluding remarks and future perspectives

In the past years major advances have been made in our understanding of plasmalogen biology. This review aimed to give an overview over the current knowledge in this field with a focus on the involvement of plasmalogens in physiological and pathophysiological processes. There is a growing body of evidence on their involvement in human diseases. New tools like the ether-lipid deficient mouse provided an important tool in this process, but in particular the evolution of lipidomics with new

Acknowledgements

This work was supported by the seventh framework program of the EU-funded “LipidomicNet” (proposal number 202272) and the BMBF network project “Systems Biology Consortium on Metabotypes (SysMBo)”.

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