title: Low density lipoprotein catabolism is enhanced by the cleaved form of alpha-1-antitrypsin.
abstract: The frequent occurrence of hypocholesterolaemia following inflammatory processes is well known but unexplained. Elevated plasma levels of serine proteinase inhibitors (serpins) and their complexes with target enzymes have been demonstrated in inflammatory, malignant and infectious diseases which are also often accompanied by low plasma cholesterol levels. Under inflammatory conditions, uncomplexed, but cleaved inactive serpins arising from slow deacylation of the serpin-proteinase complex may be present in the circulation. To determine the influence of native and cleaved forms of serpins, such as alpha-1-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 binding and internalization by 20-25%, independently of the amount of AAT added, an effect most probably due to the cleaved form of AAT produced by local proteolysis of native AAT incubated in the cell culture. Moreover we have shown that the cleaved form of AAT interacts with LDL in vitro, and that such an interaction abolishes AAT ability to stimulate LDL binding and internalization. This study for the first time describes the ability of the cleaved form of AAT to stimulate LDL binding and internalization in HepG2 cell culture, and provides evidence that hypocholesterolaemia occurring during inflammatory processes may be mediated by cleaved forms of serpins.
authors.affiliation: Department of Medicine, Lund University Hospital, Malmö, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Janciauskiene
authors.forename: O
authors.initials: O
authors.lastname: al Rayyes
authors.forename: C H
authors.initials: CH
authors.lastname: Floren
authors.forename: S
authors.initials: S
authors.lastname: Eriksson
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
chemical_list: D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin