Highly oxidized albumin is mainly cleared by mouse liver sinusoidal endothelial cells via the receptors stabilin-1 and -2

Abstract

BackgroundOxidized albumin (oxHSA) is elevated in several pathological conditions, especially those involving the liver, such as decompensated cirrhosis, acute on chronic liver failure and liver mediated renal failure. Patient derived oxidized albumin was previously shown to be an inflammatory mediator in cultured endothelial cells and leukocytes. The removal from circulation of oxidized albumins is therefore essential for maintenance of homeostasis. Normal serum levels of oxidized albumin are low, implying it is constantly eliminated. Liver sinusoidal endothelial cells (LSEC) are prominent scavenger cells in the body, specializing in the removal of macromolecules e.g. hyaluronan, denatured collagen, modified albumins, bacterial endotoxin (LPS) and oxidized lipoprotein. Given that oxidized albumin is mainly cleared by the liver, we hypothesize the LSEC are the site of uptake in the liver. Furthermore the stabilins -1 and -2 are the most prominent candidates for oxHSA uptake receptors, given their expression pattern and uptake of other ligands. MethodsIn vivo biodistribution, hepatocellular distribution and in vitro uptake studies on isolated liver cell populations or receptor expressing cell lines. ResultsIn vivo oxHSA was cleared rapidly (t1/2 <90seconds) by the liver (47% of uptake) and distributed to mainly the LSEC. In in vitro studies LSEC endocytosed oxHSA much more than other cell populations isolated from the liver. Furthermore, it was shown that the uptake was mediated by the stabilins, by inhibiting uptake in LSEC with other stabilin ligands and showing uptake in HEK cells overexpressing stabilin-1 or 2. oxHSA also inhibited the uptake of other stabilin ligands. ConclusionsLSEC and their stabilins are vital for the clearance of oxidized albumin, and therefore play a pivotal role in maintaining homeostasis.