LOW-DENSITY-LIPOPROTEIN CATABOLISM IS ENHANCED BY THE CLEAVED FORM OFALPHA-1-ANTITRYPSIN

The frequent occurrence of hypocholesterolaemia following inflammatory processes is well known but unexplained. Elevated plasma levels of se rine proteinase inhibitors (serpins) and their complexes with target e nzymes have been demonstrated in inflammatory, malignant and infectiou s diseases which are also often accompanied by low plasma cholesterol levels. Under inflammatory conditions, uncomplexed, but cleaved inacti ve serpins arising from slow deacylation of the serpin-proteinase comp lex may be present in the circulation. To determine the influence of n ative and cleaved forms of serpins, such as alpha-l-antitrypsin (AAT), on lipoprotein metabolism, we investigated the effect of these forms on low density lipoprotein (LDL) catabolism in human HepG2 cell line. We have found that the cleaved form of AAT in concentrations from 125 to 2000 nmol l(-1) stimulates LDL binding to the HepG2 cells, by up to 49% with a subsequent increase in LDL uptake and degradation of up to 79 and 65% respectively. Native AAT was also found to increase LDL bi nding and internalization by 20-25 %, independently of the amount of A AT added, all effect most probably due to the cleaved form of AAT prod uced by local proteolysis of native AAT incubated in the cell culture. Moreover, we have shown that the cleaved form of AAT interacts with L DL in vitro, and that such an interaction abolishes AAT ability to sti mulate LDL binding and internalization. This study for the first time describes the ability of the cleaved form of AAT to stimulate LDL bind ing and internalization in HepG2 cell culture, and provides evidence t hat hypocholesterolaemia occurring during inflammatory processes may b e mediated by cleaved forms of serpins.