Apolipoprotein sialic acid Directory UMM :Data Elmu:jurnal:A:Atherosclerosis:Vol154.Issue1.Jan2001:

Fig. 1. Upper Basic molecular structure for derivatives of neu- raminic acid. Variable sites are represented by an ‘R’ with a subscript indicating the carbon number to which different groups may be attached. Lower 5-N-acteylneuraminic acid, the most abundant sialic acid derivative found in human plasma. sion that individuals with low levels of lipoprotein-asso- ciated sialic acid are at increased risk of developing CHD [12 – 14]. Despite this relationship the factors that control the content of lipoprotein-associated sialic acid are not known. The factors that influence the content of lipoprotein- associated sialic acid and its relationship to lipoprotein metabolism will be the focus of this review. The discus- sion will begin with an overview of the sialic acid-con- taining components on lipoproteins apolipoprotein apo, glycolipids and their contribution to the total sialic acid content of a lipoprotein fraction, and end with the known effects that lipoprotein sialic acid has on lipoprotein metabolism. Graphical representations of some of the terms used in this manuscript are shown in Fig. 3.

2. Apolipoprotein sialic acid

Of the plasma apolipoproteins, apo A-II, B-48, B- 100, C-II, C-III, D, E, J, and a have been reported to be sialylated to some degree Table 1 [15 – 25]. Other minor sialylated apolipoproteins including apo C-IV, H and M have been described but will not be discussed further [26 – 28]. Many sialylated apolipoproteins, with the exceptions of apo B-100, and, possibly, B-48, D, J, and a, are found in plasma as a mixture of glycosylated and non-glycosylated forms [17,21,29 – 31]. The significance of the heterogeneity in the glycosylation of proteins, in general, is not known and has been discussed by Dwek et al. [32]. The existence of non-glycosylated forms of some apolipoproteins in plasma would imply that gly- cosylation and sialylation are not requirements for their secretion. This has been shown to be true for those apolipoproteins where this hypothesis has been tested [30,33]. Other potential functions of sialic acid on indi- the two categories. One type of study has focused on the relationship between plasma sialic acid and CHD. The majority of these studies have found that plasma sialic acid levels are increased in individuals with CHD, possibly due to elevations of plasma acute phase proteins released in response to inflammation [9 – 11]. The other type of study relating sialic acid to CHD has focused on the relationship between lipoprotein-associ- ated sialic acid and the development of CHD. This latter type of study has generally arrived at the conclu- Fig. 2. Examples of lipid-bound A and protein-bound B sialic acids. Individual sugars and linkages are detailed. Neu5Aca2 “ 3Gal represents an a-linkage between carbon 2 of 5-N-acetylneuraminic acid sialic acid and carbon 3 of galactose. Panel A is ganglioside GM 3 and panel B is a complex bi-antennary oligosaccharide of the type found on apo B-100. Abbreviations used: Asn, asparagine; Gal, galactose; Glc, glucose; GlcNAc, N-acetylglucosamine; Man, mannose; Neu5Ac, 5-N-acetylneuraminic acid. Fig. 3. Examples to illustrate some terms used throughout the manuscript. All figures show a protein curved line that can be glycosylated with a neutral oligosaccharide core structure open hexagons and sialic acid filled hexagons. A, B Di-sialylated proteins containing A a single di-sialylated oligosacharide or B two mono-sialylated oligosaccharides, C mono-sialylated protein, D, lower left desialylated protein, and E non-sialylated protein. A-IA-II HDL particles is reported to be non-glycosy- lated [33]. 2 . 2 . Apolipoprotein B Apo B-100 is a multi-sialylated apolipoprotein con- taining several mono- and di-sialylated complex bi-an- tennary oligosaccharides in addition to non-sialylated, high-mannose structures [19,20]. Bartlett and Stanley [34] have shown that all low density lipoprotein LDL contain mono-sialylated complex bi-antennary oligosac- charides. Since these structures are not found on gan- gliosides the conclusion can be drawn that all circulating apo B-100 polypeptides contain at least one sialic acid residue [35]. Further characterization of the heterogeneity in the sialylation of apo B-100 might best be accomplished by studying the sialylation of individ- ual peptide fragments following partial proteolysis of apo B-100. This would allow individual apo B-100 peptide sequences to be associated with different glyco- sylation and sialylation patterns. In rabbits, the number of complex bi-antennary oligosaccharides on apo B-100 containing two terminal sialic acids is variable, being lower in those animals with elevated cholesterol levels [36,37]. The proposed structure of this di-sialylated oligosaccharide Fig. 2, which is also found on human apo B-100, is identical to the two complex bi-antennary oligosaccharides found on human transferrin [38]. It is worth noting that the number of di-sialylated oligosaccharide chains on trans- ferrin is related to plasma cholesterol levels although it is not known if there is any relationship between the glycosylation of transferrin and apo B-100 [39]. Sasak et al. [18] also studied the carbohydrate content of apo B-48 and identified mono- and di-sialylated oligosac- charides that are of similar composition to those found on apo B-100. 2 . 3 . Apolipoprotein C-II Apo C-II is found in di-, mono- and non-sialylated forms in plasma [21]. The non-sialylated form is non- glycosylated [21]. The mono-sialylated and di-sialylated forms of apo C-II constitute a small percentage B 15 of the total apo C-II in plasma [21]. While the sialylated forms of apo C-II have been described as precursors i.e. propeptide to the parent polypeptide, it is possible that mature apo C-II includes these sialy- lated forms in addition to non-glycosylated forms. The significance of the sialylation of apo C-II is unknown [21,40]. 2 . 4 . Apolipoprotein C-III Apo C-III exists as three isoforms in plasma, apo C-III , C-III 1 and C-III 2 , the subscripts indicating the vidual apolipoproteins are discussed below. The study of apolipoprotein sialylation is complicated due to spe- cies-related and tissue-related differences in glycosyla- tion and sialylation [32]. This review will focus on the sialylation of apolipoproteins isolated from human plasma unless otherwise indicated. 2 . 1 . Apolipoprotein A-II The proportion of plasma apo A-II that is sialylated is relatively low with less than 1 being either mono- sialylated or di-sialylated [17]. The non-sialylated frac- tion is non-glycosylated [17]. The glycosylated form of apo A-II has been shown to influence the lipid-binding of the apolipoprotein and binds better to the high density lipoprotein HDL subfraction HDL3 than the non-glycosylated form, although it is not known if this is a sialic acid-related effect [33]. Apo A-II from apo number of sialic acid residues per polypeptide [41]. The non-sialylated form apo C-III is not glycosylated [29]. Hypertriglyceridemic subjects have an increased proportion of apo C-III as the C-III 2 isoform in very low density lipoprotein VLDL [42,43]. This may be due to apo C-III 2 having a higher affinity for VLDL than apo C-III or C-III 1 , [44]. Apo C-III 2 is also a poorer inhibitor of VLDL binding to the purported lipolysis stimulated receptor than apo C-III or C-III 1 , [44]. Neuraminidase treatment of apo C-III to remove sialic acid has no effect on the ability of apo C-III to inhibit lipoprotein lipase [45]. 2 . 5 . Apolipoprotein D Apo D, found primarily on HDL, is a highly glycosy- lated apolipoprotein 18 by weight [23]. The different isoforms of apo D have been shown, in part, to be due to differences in the sialic acid content of apo D [31,46]. Schindler et al. [47] has shown that there are a wide range of carbohydrate structures with different num- bers of sialic acid residues that can occupy each of the two glycosylation sites. The significance of sialic acid on apo D is unknown. 2 . 6 . Apolipoprotein E Apo E occurs as di-, mono-, and non-sialylated forms in plasma, the non-sialylated form being non-gly- cosylated [30]. The metabolism of apo E in plasma is related to its degree of sialylation with the di-sialylated isoform cleared from plasma more rapidly than the non-sialylated isoform [48]. Marmillot et al. [49] re- ported that sialylated apo E had a higher affinity for HDL than desialylated apo E in vitro while in vivo studies have not shown any differences in the lipo- protein distribution of disialylated and non-sialylated apo E [48]. Long-term ethanol intake leads to decreased apo E sialylation in rats similar to what has been observed with apo J in rats [50,51]. 2 . 7 . Apolipoprotein J Apo J is a sialylated apolipoprotein found on HDL [25]. Apo J sialylation in rats is alcohol sensitive, there being decreased in sialylation of the apolipoprotein following long-term ethanol intake [51]. The signifi- cance of sialic acid on apo J is unknown. 2 . 8 . Apolipoprotein a Apo a is the most highly sialylated apolipoprotein [15,16]. The sialic acid content of apo a is influenced by two factors, the number of kringle repeats in the apolipoprotein i.e. the length of the apolipoprotein and the degree of sialylation of each kringle [52]. The sialylation of apo a has been shown to inhibit its secretion from HepG2 cells [53]. There is no require- ment of sialic acid on apo a for the formation of Lpa from apo a and LDL [53]. While there are no reports of the effect of sialylation on the clearance rate of free apo a in plasma, desialylation of plasminogen, which is in part homogeneous to apo a, has been reported to increase its clearance rate in plasma [54]. Sialic acid is required for the interaction between apo a and complement activation fragment iC3b although the significance of this interaction is unknown since there is no effect of apo a sialylation on compliment activation or degradation [55].

3. Glycolipid sialic acid

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