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论文类型：期刊论文

发表时间：2017-05-15

发表刊物：LIFE SCIENCES

收录刊物：SCIE、PubMed、Scopus

卷号：177

页面范围：27-40

ISSN号：0024-3205

关键字：7-Ketocholesteryl-9-carboxynonanoate; Oxidized low-density lipoprotein; LOX-1; PPAR gamma; ABCA1

摘要：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 alpha and ABCA1 protein expression induced by oxLig-1 or methylated oxLig-1 was measured by western blotting. In addition, PPAR gamma 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 gamma and LXR alpha and specific siRNAs against LOX-1, PPAR gamma and LXR alpha.
   Key findings: Docking, fluorescence immunocytochemistry and ELISA analyses showed that oxLig-1 bound LOX-1 and that the omega-carboxyl group was critical for this binding. Moreover, oxLig-1, but not methylated oxLig-1, increased LOX-1, LXR alpha, and ABCA1 expression. Luciferase reporter assays indicated that oxLig-1 activated PPAR gamma in the presence of LOX-1. Additionally, the inhibitor and siRNA experiments showed that oxLig-1 triggered the PPAR gamma-LXR alpha 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 gamma signal transduction to upregulate the expression of ABCA1. (C) 2017 Elsevier Inc. All rights reserved.