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

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

Lipid associated sialic acids are found on gan- gliosides, a family of glycolipids somewhat similar in structure to phospholipids that have a variable sialic acid-containing oligosaccharide structure attached to an acylated ceramide core Fig. 2 [56]. Although syn- thesized to a large degree by neural tissue, plasma gangliosides are primarily liver-derived [56,57]. More than ten different gangliosides have been identified in Table 1 A summary table of the sialylation of sialylated apolipoprotein constituents of plasma lipoproteins Number of sialic acid residues per Approximate percentage Apolipoprotein Average sialic acids per Reference Glycation non-sialylated a polypeptide a mole protein a linkage 0–2 99 B 0.001 A-II O [17,33] 12–14 B-100 13 N [20,34] 1.7 [18] Unknown Unknown B-48 N 0–2 85 C-II 0.23 Unknown [21] C-III 0–2 7.5 1.27 O [22,29] D 0–6 Unknown 5.4 N [23,31,47] 0–2 80 E 1.29 O [30] J Unknown Unknown N [25] Unknown a b 5.7 5.7 N [15,16,52] a Values for proteins isolated from human plasma. b Estimated number of sialic acid residues per kringle IV repeat. plasma, the majority of which are associated with lipo- proteins Table 2 [58,59]. Gangliosides are likely to be present on newly secreted lipoproteins although there may also be transfer of gangliosides to lipoproteins in plasma. The synthesis of plasma gangliosides requires the addition of sialic acid to glycolipid core structure. This reaction is under control of hepatic sialyltransferases, a family of enzymes that sialylate glycoproteins and gan- gliosides [60,61]. The expression of individual sialyl- transferases is unregulated in certain disease states resulting in an overproduction of individual gan- gliosides that increases the concentration of gan- gliosides in plasma [6]. Gangliosides are able to influence lipoprotein metabolism, though the mechanisms involved are not known. Filipovic et al. [62] showed that incubation of LDL with ganglioside inhibits its binding and uptake by smooth muscle cells. Subsequent removal of the sialic acid from the ganglioside-enriched LDL with neuraminidase abolished the inhibitory effect on the uptake of LDL by smooth muscle cells. Neither free sialic acid nor other negatively charged amphipathic molecules incubated with LDL had any effect on their uptake by smooth muscle cells demonstrating a gan- glioside-specific effect. Millar et al. [63] showed that incubation of LDL with ganglioside resulted in a de- creased interaction between LDL and arterial proteo- glycans while incubation with asialoganglioside resulted in a slightly increased interaction. Thomas and Poznan- sky [64] have demonstrated that the addition of gan- gliosides to lipid vesicles resulted in increased cholesterol transfer suggesting that lipoprotein-associ- ated gangliosides can influence the activity of cholesteryl ester transfer protein CETP.

4. Sialylation of lipoproteins