LAUSR

Aim: Lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1), a specific membrane receptor for oxidized low‐density lipoprotein (oxLDL), plays a crucial role in atherosclerosis progression. The aim of this study was to elucidate the role of 7‐ketocholesteryl‐9‐carboxynonanoate (oxLig‐1), a lipid component of oxLDL, in the binding of oxLDL to LOX‐1 and to determine whether oxLig‐1 binding to LOX‐1 is involved in the upregulation of ABCA1 expression. Main methods: OxLig‐1 binding to LOX‐1 was analysed by AutoDock 4.2.6 and confirmed by fluorescence immunocytochemistry and enzyme‐linked immunosorbent assays (ELISAs). LOX‐1, LXR&agr; and ABCA1 protein expression induced by oxLig‐1 or methylated oxLig‐1 was measured by western blotting. In addition, PPAR&ggr; activation was investigated using a dual‐luciferase reporter system. Furthermore, the signalling cascade involved in oxLig‐1‐induced ABCA1 expression was assessed using inhibitors for PPAR&ggr; and LXR&agr; and specific siRNAs against LOX‐1, PPAR&ggr; and LXR&agr;. Key findings: Docking, fluorescence immunocytochemistry and ELISA analyses showed that oxLig‐1 bound LOX‐1 and that the &ohgr;‐carboxyl group was critical for this binding. Moreover, oxLig‐1, but not methylated oxLig‐1, increased LOX‐1, LXR&agr;, and ABCA1 expression. Luciferase reporter assays indicated that oxLig‐1 activated PPAR&ggr; in the presence of LOX‐1. Additionally, the inhibitor and siRNA experiments showed that oxLig‐1 triggered the PPAR&ggr;‐LXR&agr; signalling pathway, leading to upregulation of ABCA1, and that this process required the participation of LOX‐1. Significance: Our observations indicate that oxLig‐1 is a critical epitope of oxLDL that mediates the binding of oxLDL to LOX‐1 and initiates PPAR&ggr; signal transduction to upregulate the expression of ABCA1.