Page 42 - Read Online

Sobenin et al. Desialylated LDL in diabetes

acetylation, metal-dependent oxidation, methylation, particle size on its binding, uptake, and internalization
malonic dialdehyde treatment, etc.) lead to the formation by cells; such explanation was provided only for
of anionic LDL thus rendering it atherogenic. [31] It is desialylated LDL. [37]
possible that LDL surface charge plays a significant role
in the processes of lipoprotein-to-cell interaction, and Interestingly, LDL desialylation is assumed to be a
charge alterations may substantially modify LDL cellular systemic process, which affects not only LDL as a
metabolism, thus resulting in lipid deposition. The single target. Recently Koska et al. [38] have reported
elevated electrophoretic mobility of desialylated LDL that properly glycosylated apoC-III proteoform (i.e.
may be readily explained considering the significantly apoprotein-bearing 2 sialic acid residues per every
reduced content of free amino groups of desialylated biantennary polysaccharide chain), in contrast
apoB. [30,31] to partially or totally desialylated proteoforms, is
associated with beneficial lipid profile in prediabetic
A smaller size and increased density of desialylated and type 2 diabetic patients. It is possible that apoC-
LDL particles seem to be typical attributes of modified III non-sialylated, monosialylated, and di-sialylated
atherogenic LDL. [18,31] In our study, LDL’s ability to isoforms occur in circulation owing to desialylation (or
induce intracellular cholesterol accumulation increased another kind of deglycosylation), but not because of
with LDL density. Desialylated LDL of lower density different pathways of posttranslational glycosylation in
was not atherogenic, and the densest sialylated LDL hepatocytes.
was capable of inducing a moderate increase in
cellular cholesterol. However, this does not necessarily This study has certain limitations. First, it was of an
imply that the density or size of LDL particles are experimental nature, and not aimed at estimating the
the primary determinants of their atherogenicity. As clinical relevance of desialylated LDL with respect to
it was demonstrated previously, desialylated LDL diabetes and/or gender- and age-related differences, or
is also characterized with decreased content of association with metabolic control and therapy. Second,
neutral sugars such as galactose and mannose and it was not possible to calculate the sample size prior to
acetylated residues such as N-acetylglucosamine. [31] the study, because there were no available statistical
It may be speculated that some extensively modified data on variability of the studied parameters in healthy
LDL particles may be deprived of not only sialic acid, subjects and diabetic patients. Thus, only post hoc
but also of galactose residues, that usually become analysis was possible, which showed that the given
sample size was sufficient to reach 96-100% statistical
terminal saccharides in biantennary polysaccharide power at a 5% confidence level, with respect to
chains in apoB after desialylation. Such particles observed inter-groups differences in LDL atherogenicity,
cannot be isolated from the total LDL preparation by electrophoretic mobility of desialylated LDL, and intra-
RCA 120 affinity chromatography and would contaminate group differences between sialylated and desialylated
non-bound LDL fractions that are generally thought to LDL particle sizes. Regardless, the results of our study
be non-modified, sialic acid-rich LDL. Assuming that conclude that there is a fraction of modified LDL along
diminished particle size, increased density, and loss with native LDL in the blood of diabetic patients. This
of sugar residues are the processes characteristic for naturally occurring modified LDL is characterized by
LDL modification and work in parallel, the densest part various alterations to its physicochemical properties.
of non-bound (so-called sialylated) LDL would contain Our previous findings have shown that: (1) it is
some amount of exceptionally modified LDL that could desialylated and non-enzymatically glycated lipoprotein;
raise the intracellular cholesterol levels. Additionally, (2) it is characterized by lowered esterified cholesterol
desialylated or sialylated LDL from diabetic patients level and elevated content of lyso-phospholipids; and
did not differ significantly with respect to particle (3) it is atherogenic in terms of intracellular cholesterol
size from corresponding LDL fractions from healthy accumulation. We believe our research presents new
subjects; the difference, however, was dramatic with and significant abnormal peculiarities of this LDL: (1) it
regard to the atherogenic effect. Therefore, the size is a small, dense LDL; and (2) it is more electronegative
or density of LDL particles may be regarded as the than native LDL. Therefore, previously described
marker of LDL atherogenic modification, but seem atherogenic LDL fraction in diabetics can be regarded
to be secondary events reflecting the alterations in as multiple-modified LDL that may be assigned to have
chemical composition of LDL that have occurred a significant role in early atherogenesis in diabetes
before. However, it may be speculated that smaller mellitus. The origin and metabolic fate of this in vivo
LDL particle size may lead to conformational changes modified LDL remains to be studied.
in those apoB domains responsible for interaction
with cell receptors. However, in this case, one should Acknowledgments
provide mechanistic explanations of the effect of LDL We acknowledge the help of Dr. Olli Jaakkola and
Vessel Plus ¦ Volume 1 ¦ March 31, 2017 35