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Uremia-induced lysine modifications transform plasma albumin into a high-density lipoprotein receptor inhibitor
BMC Pharmacology and Toxicology volume 13, Article number: A40 (2012)
Protein damage induced by retained uremic solutes may be an important component in the pathophysiology of advanced renal disease. Albumin isolated from hemodialysis patients was recently shown to block high-density lipoprotein (HDL) receptor-mediated cholesterol uptake. However, post-translational modifications that render albumin a scavenger receptor class B type I (SR-BI) ligand are not known. We hypothesized that the elimination of positive charge through oxidation of albumin-lysine residues is required to generate recognition motifs for SR-BI. Since carbamylation and carboxymethylation are major lysine modifications in vivo, we aimed at investigating their influence on the binding properties of HD-albumin to SR-BI.
Albumin from HD patients and control subjects was isolated from serum by affinity chromatography. Mass spectrometry was used to study structurally defined lysine modifications on HD-albumin. Competition experiments (displacement of Alexa-labeled HDL) were performed to assess binding affinity of modified albumin to SR-BI.
We identified a significant increase in 3-chlorotyrosine, carbamyllysine and carboxymethyllysine content on HD-albumin. Competition experiments revealed that chlorolysine and carbamyllysine mediate binding of AOPP-albumin to SR-BI whereas binding properties of carboxmethyllysine did not differ significantly from native albumin.
Oxidation and carbamylation of serum albumin generate relevant SR-BI antagonists in renal disease that may interfere with SR-BI-mediated reverse cholesterol transport. Displacement of HDL from its major receptor may result in decreased hepatic cholesterol uptake, depressed HDL metabolism and abnormal HDL composition and function. Dysfunctional reverse cholesterol transfer may contribute to the excessive cardiovascular mortality observed in patients suffering from renal disease.
This work was supported by the Austrian Science Fund FWF (grants P21004-B02, P-22521-B18 and P22976-B18), and the PhD Program MOLMED of the Medical University of Graz.
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Binder, V., Holzer, M., El-Gamal, D. et al. Uremia-induced lysine modifications transform plasma albumin into a high-density lipoprotein receptor inhibitor. BMC Pharmacol Toxicol 13, A40 (2012). https://doi.org/10.1186/2050-6511-13-S1-A40
- Competition Experiment
- Reverse Cholesterol Transport
- Cholesterol Uptake
- Hepatic Cholesterol
- Scavenger Receptor Class