removed by the reticuloendothelial system. Lindbohm et al. [93] studied the clearance of native LDL contain-
ing varying amounts of sialic acid and found that there was no effect of sialic acid content on LDL clearance.
Desialylation of LDL had no effect on its binding and uptake by fibroblasts or hepatocytes [82,99]. How-
ever desialylated LDL and sialic acid-poor LDL both show an enhanced uptake by aortic smooth muscle cells
[12,62]. Enrichment of LDL with ganglioside to in- crease its sialic acid content decreased LDL uptake by
aortic smooth muscle cells [62]. The reasons for the differences in uptake by the different cell types may be
due to the differential expression of lipoprotein recep- tors. Grewal et al. [85] have hypothesized the clearance
of desialylated LDL via a lectin receptor. Yoshida et al. [100] recently described a lipoprotein receptor, LOX-1,
that recognizes oxidized LDL. This receptor is ho- mologous to the natural killer cell antigen NKR-P1,
which has lectin-like qualities [101]. Since sialic acid- poor LDL have many of the qualities of oxidized LDL
the possibility that the enhanced uptake of desialylated and sialic acid-poor LDL is due to oxidation rather
than decreased sialylation or desialylation must be con- sidered [102]. It may be worthwhile to investigate if
differences in binding and uptake are found with LDL that has been desialylated and subsequently resialy-
lated. This would enable oxidative effects to be distin- guished from sialic acid-specific effects.
Camejo et al. [94] first reported that desialylation of LDL increased its interaction with chondroitin-6-sul-
fate-rich proteoglycans isolated from arterial wall ma- trix. Enrichment of LDL with gangliosides decreased
the interaction of LDL with chondroitin-6-sulfate-rich proteoglycans [63]. However there is no difference in
the interaction of LDL with relatively low and high sialic acid content isolated from separate individuals
[63]. This suggests that individual sialic acid-containing components on LDL rather than total LDL sialic acid
can affect the interaction of LDL with chondroitin-6- sulfate-rich proteoglycans.
7. Lpa sialic acid
Among lipoproteins, Lpa is the most highly sialy- lated Table 3. Lpa sialic acid is derived primarily
from apo a, with gangliosides and apo B-100 also making contributions. Apo B-100 derived from Lpa
has the same carbohydrate content, including sialic acid, as apo B-100 from LDL [103]. Presumably the
ganglioside content of Lpa is also similar to that of LDL. The major difference in the sialic acid content
between Lpa and LDL is the contribution of sialic acid from apo a in Lpa. The sialic acid content of
Lpa should vary depending on the kringle length of the apo a polypeptide [52]. The association of apo a
with LDL to form Lpa is not dependent on the sialylation of apo a [53].
Tertov and Orekhov [97] demonstrated that Lpa from healthy subjects did not cause lipid accumulation
in aortic smooth muscle cells. However, Lpa from subjects with CHD, which was relatively poor in sialic
acid, did result in cholesterol accumulation in cultured aortic smooth muscle cells. Desialylation of Lpa also
resulted in lipid accumulation in this cell type. These authors also divided LDL from a single donor into
sialic acid-poor and sialic acid-rich fractions. The sialic acid-poor fraction resulted in lipid accumulation and
was prone to aggregation while the sialic acid-rich fraction had neither of these effects [97]. Due to similar-
ities between LDL and Lpa the possibility of these effects being due to oxidation should be considered.
8. HDL sialic acid
The major contributors of sialic acid on HDL are apo C-III, E, J and gangliosides. Due to the large
variation of HDL sizes and protein contents within each size range it is difficult to calculate an average
HDL sialic acid content. Lindbohm et al. [93] reported that subjects with combined hyperlipidemia had higher
sialic acid per HDL protein than subjects with primary hypercholesterolemia although the significance of this is
unclear. The only known function of sialic acid on HDL metabolism is related to apo E [48]. Phospholipid
vesicles enriched with sialylated apo E were better at promoting cholesteryl ester uptake from HDL to
HepG2 cells than neuraminidase treated desialylated HDL or vesicles enriched with desialylated apo E.
Vesicles containing apo E that had been desialylated and
then resialylated
also resulted
in enhanced
cholesteryl ester uptake by HepG2 cells demonstrating a sialic acid-specific effect.
9. Future areas of research