Factors Affecting S-Homocysteinylation of LDL Apoprotein B

Abstract

Background: Hyperhomocysteinemia is an important risk factor for vascular disease and atherosclerosis, but the mechanisms by which homocysteine exerts its deleterious effects are not known. Because oxidation and/or homocysteinylation may increase atherogenicity of LDL, we investigated S-homocysteinylation of LDL as a possible contributor to atherosclerosis pathogenesis. Methods: We used capillary electrophoresis to measure LDL-bound thiols [homocysteine, cysteine (Cys), cysteinylglycine, glutathione, and glutamylcysteine] in 104 healthy study participants We also assessed total plasma thiol concentrations and lipid profiles. Results: Our data suggest that apoprotein B (apoB)-cysteinylglycine (CysGly), apoB-Hcy, and apoB-Cys concentrations are markedly higher in men than in women. The percentage of CysGly and glutathione on apoB was higher than that of the same thiols in plasma, whereas the other thiols were markedly less prevalent in lipoprotein than in plasma. Pearson correlation showed that among all thiols, only total plasma Hcy is related to apoB-Hcy concentrations. Multiple correlation analysis confirmed that total Hcy was the most important determinant of apoB-Hcy. Age and LDL cholesterol also showed positive associations, but Cys and, mainly, CysGly were negatively associated with apoB-Hcy concentrations. Conclusions: apoB-Hcy derivative formation is mainly dependent on total homocysteine concentration. Increased cholesterol concentrations are related to increased apoB-Hcy. CysGly seems to compete with Hcy for binding to LDL apoprotein, suggesting that CysGly

Increased Low-Density Lipoprotein S-Homocysteinylation in Chronic Kidney Disease

“…By multiple regression analysis it also emerged that, as for the normal population, Cys-Gly seemed to inhibit the interaction between Hcy and LDL also in CKD, thus confirming our previous hypothesis on the possible protective role of this molecule toward the proatherogenic modification of LDL [22,23]. We found that the relative quantity of Cys-Gly is higher in the apoprotein fraction than in plasma both in controls and CKD patients, thus confirming our previous data on the high affinity of apoB for Cys-Gly.…”

“…Fibronectin and factor Va are examples of plasma proteins that undergo S-linked homocysteinylation with possible functional consequences. We have recently demonstrated that plasma lipoproteins are also susceptible to S-homocysteinylation [21,22]. Given that at least 5 low molecular mass aminothiols occur in plasma, Hcy competes with other thiols for binding to the accessible –SH sites.…”

“…We found that the relative quantity of Cys-Gly is higher in the apoprotein fraction than in plasma both in controls and CKD patients, thus confirming our previous data on the high affinity of apoB for Cys-Gly. On the contrary, it has been amply reported that albumin shows an elevated affinity principally for Cys and Hcy [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Unusually, the unpaired Cys34 of albumin have a p K a <6 [15].…”

“…We have only recently described the first method which enables the simultaneous determination of all the thiols linked to LDL apoprotein by S-linkage [21]. This allowed us to investigate the levels of all aminothiols bound to LDL in a group of healthy subjects to define their normal levels in vivo[22]. Our results showed that increasing concentrations of plasma Hcy lead to higher S-homocysteinylation of lipoprotein in vivo.…”

A urinary metabolomics (GC-MS) strategy to evaluate the antidepressant-like effect of chlorogenic acid in adrenocorticotropic hormone-treated rats

“…52 Meanwhile, it is an inhibitory neurotransmitter in the brain and an important participant and regulator in glucose metabolism. 53 As a major energy source, alanine might enter tricarboxylic acid (TCA) cycle and glucose in gluconeogenesis.…”