International Journal of Molecular Sciences Review The Role of ApoE Expression and Variability of Its Glycosylation in Human Reproductive Health in the Light of Current Information Monika Kacperczyk, Agnieszka Kmieciak and Ewa Maria Kratz * Department of Laboratory Diagnostics, Division of Laboratory Diagnostics, Faculty of Pharmacy, Wroclaw Medical University, Borowska Street 211A, 50-556 Wroclaw, Poland; [email protected] (M.K.); [email protected] (A.K.) * Correspondence: [email protected] Abstract: Apolipoprotein E (ApoE), a 34-kDa glycoprotein, as part of the high-density lipoprotein (HDL), has antioxidant, anti-inflammatory and antiatherogenic properties. The variability of ApoE expression in the course of some female fertility disorders (endometriosis, POCS), and other gyneco- logical pathologies such as breast cancer, choriocarcinoma, endometrial adenocarcinoma/hyperplasia and ovarian cancer confirm the multidirectional biological function of ApoE, but the mechanisms of its action are not fully understood. It is also worth taking a closer look at the associations between ApoE expression, the type of its genotype and male fertility disorders. Another important issue is the variability of ApoE glycosylation. It is documented that the profile and degree of ApoE glycosylation varies depending on where it occurs, the type of body fluid and the place of its synthesis in the human body. Alterations in ApoE glycosylation have been observed in the course of diseases such as Citation: Kacperczyk, M.; Kmieciak, preeclampsia or breast cancer, but little is known about the characteristics of ApoE glycans analyzed A.; Kratz, E.M. The Role of ApoE in human seminal and blood serum/plasma in the context of male reproductive health. A deeper Expression and Variability of Its analysis of ApoE glycosylation in the context of female and male fertility will both enable us to Glycosylation in Human broaden our knowledge of the biochemical and cellular mechanisms in which glycans participate, Reproductive Health in the Light of having a direct or indirect relationship with the fertilization process, and also give us a chance of con- Current Information. Int. J. Mol. Sci. 2021, 22, 7197. https://doi.org/ tributing to the enrichment of the diagnostic panel in infertile women and men, which is particularly 10.3390/ijms22137197 important in procedures involved in assisted reproductive techniques. Moreover, understanding the mechanisms of glycoprotein glycosylation related to the course of various diseases and conditions, Academic Editors: Udo Jeschke and including infertility, and the interactions between glycans and their specific ligands may provide us Purusotam Basnet with an opportunity to interfere with their course and thus develop new therapeutic strategies. This brief overview details some of the recent advances, mainly from the last decade, in understanding Received: 11 May 2021 the associations between ApoE expression and some female and male fertility problems, as well as Accepted: 1 July 2021 selected female gynecological diseases and male reproductive tract disorders. We were also interested Published: 4 July 2021 in how ApoE glycosylation changes influence biological processes in the human body, with special attention to human fertility. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Keywords: apolipoprotein E; ApoE concentration; ApoE glycosylation; human fertility; reproductive published maps and institutional affil- tract disorders iations. 1. Introduction Copyright: © 2021 by the authors. Apolipoprotein E (ApoE) is a 34-kDa glycoprotein. The primary translation product Licensee MDPI, Basel, Switzerland. consists of 317 amino acids and includes an 18-amino acid signal peptide [1], and a mature This article is an open access article ApoE is composed of 299 amino acids [2]. Physiologically, ApoE does not cross the blood– distributed under the terms and brain barrier (BBB), but is present both in the periphery and in the central nervous system conditions of the Creative Commons Attribution (CC BY) license (https:// (CNS) [3]. Around the perimeter, ApoE is secreted from many cells throughout the human creativecommons.org/licenses/by/ body, such as hepatic parenchymal cells, monocytes, macrophages, adipocytes and muscle 4.0/). cells [4]. In the CNS the astrocytes, vascular mural cells, pericytes, oligodendrocytes and Int. J. Mol. Sci. 2021, 22, 7197. https://doi.org/10.3390/ijms22137197 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 15 body, such as hepatic parenchymal cells, monocytes, macrophages, adipocytes and mus‐ cle cells [4]. In the CNS the astrocytes, vascular mural cells, pericytes, oligodendrocytes and choroid plexus are the main suppliers of ApoE [5,6]. Peripheric ApoE and the ApoE of CNS differ in their structure [7] and the CNS ApoE is more highly glycosylated on the C‐terminal part of the protein chain, which has a large impact on its function [8]. Int. J. Mol. Sci. 2021, 22, 7197 ApoE consists of two primary domains linked by a flexible loop region, each charac2 of 15‐ terized by a distinct structure and function [1,2] (see Figure 1). The N‐terminal domain, including a four antiparallel helix bundle, comprises the receptor‐binding region (136–150 choroidaa) and plexusthe heparan are the sulphate main suppliers proteoglycans of ApoE (HSPGs) [5,6]. Periphericbinding region ApoE [9]. and The the C‐ ApoEterminal of CNSdomain differ consists in their of amphipathic structure [7] α‐ andhelices, the CNS the high ApoE affinity is more lipid highly‐binding glycosylated region (244–272 on the C-terminalaa), and the part region of the responsible protein chain, for ApoE which self has‐association a large impact (267–299 on its aa) function [10]. ApoE [8]. is coded by geneApoE 19q13.32 consists on of the two long primary arm of domains chromosome linked 19 by [11,12], a flexible and the loop ApoE region, gene each is associ char-‐ acterizedated with byanother a distinct apolipoprotein structure and gene, function ApoC‐I [[13].1,2] (seeHuman Figure ApoE1). is The characterized N-terminal by do- its main,polymorphic including nature a four and antiparallel three allelic helix variants bundle, occur comprises in the gene the of receptor-binding this protein at the region single (136–150gene locus, aa) namelyand the ɛ2, heparan ɛ3 and sulphateɛ4 [14]. They proteoglycans encode the (HSPGs) ApoE isoforms binding E2, region E3 and [9 ].E4, The re‐ C-terminalspectively. domainBetween consists the isoforms of amphipathic differencesα-helices, were found the high in affinityamino acid lipid-binding substitutions region in (244–272the 112 and aa), 158 and positions the region [15]. responsible ApoE2 possesses for ApoE a self-association cysteine at both (267–299 positions, aa) ApoE3 [10]. ApoE pos‐ issesses coded a bycysteine gene 19q13.32at 112, but on an the arginine long arm at of 158, chromosome and ApoE4 19 possesses [11,12], and an thearginineApoE geneat both is associatedpositions [11]. with ApoE3 another is apolipoprotein the most common gene, isoform,ApoC-I [occurring13]. Human in 70–80%ApoE is characterizedof the human bypopulation its polymorphic [16]. ApoE1, nature ApoE5 and three and allelic ApoE7 variants are rare occur isoforms, in the which gene of have this different protein at vari the‐ singleants of gene amino locus, acid namely substitution"2, "3 [17]. and "Additionally,4 [14]. They encodea number the of ApoE point isoforms mutations E2, of E3 ApoE and E4,are respectively.observed, notable Between among the isoforms which is differences the Christchurch were found mutation. in amino In this acid rare substitutions variant of inApoE2, the 112 a substitution and 158 positions of Arg136 [15].Ser ApoE2 occurs possesses [18]. The a Christchurch cysteine at both mutation positions, may contrib ApoE3‐ possessesute to the a pathogenesis cysteine at 112, of but type an III arginine hyperlipoproteinemia at 158, and ApoE4 [19], possesses and probably an arginine plays at an both as positionsyet unclear [11 role]. ApoE3 in the development is the most common of Alzheimer’s isoform, disease occurring (AD) in [20,21]. 70–80% of the human populationThis short [16]. review ApoE1, details ApoE5 some and ApoE7of the recent are rare advances, isoforms, mainly which from have differentthe last ten variants years, offocusing amino on acid the substitution question of [ 17how]. Additionally, ApoE and its aglycosylation number of point changes mutations influence of ApoEbiological are observed,processes notablein the human among body, which especially is the Christchurch with regard mutation. to human In thisfertility rare variantand reproductive of ApoE2, ahealth substitution disorders. of Arg136–Ser Taking into occurs account [18 that]. The the Christchurch above topics mutation are not very may deeply contribute explored, to the pathogenesisthey may constitute of type an III interesting hyperlipoproteinemia aim for future [19 research], and probably and open plays new anopportunities as yet unclear for rolethe explanation in the development of some ofof Alzheimer’sthe molecular disease mechanisms (AD) [20 of,21 ApoE]. action. FigureFigure 1.1. SchematicSchematic structurestructure ofof ApoE.ApoE. PossiblePossible O-glycosylationO‐glycosylation sites:sites: Thr8,Thr8, Thr18,Thr18, Thr194,Thr194, Ser197,Ser197, Thr289,Thr289, Ser290Ser290 andand Ser296Ser296 [[7].7]. The Christchurch mutation results inin a Arg136–SerArg136Ser substitutionsubstitution