Antioxidative activity of high-density lipoprotein (HDL): Mechanistic insights into potential clinical benefit.
Antioxidative activity of high-density lipoprotein (HDL): Mechanistic insights into potential clinical benefit.
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DOI：
10.1016/j.bbacli.2017.07.002
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Kontush A
中科院分区：
文献类型：
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作者：
Brites F;Martin M;Guillas I;Kontush A
巨噬细胞对低密度脂蛋白（LDL）颗粒的摄取是动脉粥样硬化斑块发展的关键步骤，导致泡沫细胞形成。然而，LDL的化学修饰是诱导这一过程所必需的。致动脉粥样硬化的LDL修饰包括聚集、酶消化和氧化。通过单电子（自由基）和双电子氧化剂的LDL氧化显著增加LDL对巨噬细胞清道夫受体的亲和力，导致LDL快速摄取和脂肪条纹形成。循环高密度脂蛋白（HDL）颗粒，主要是小的、致密的、富含蛋白质的HDL 3，为LDL提供有效的保护，使其免受自由基的氧化损伤，从而抑制促炎性氧化脂质的产生。HDL介导的脂质氢过氧化物失活涉及它们最初从LDL转移到HDL，随后被载脂蛋白A-I的氧化还原活性Met残基还原为无活性的氢氧化物。几种HDL相关酶在HDL 3中的浓度相对于大、轻HDL 2升高，并且可能参与短链氧化磷脂的失活。因此，HDL是一种多分子复合物，能够获得和灭活致动脉粥样硬化脂质。在多种代谢和炎症性疾病中，高密度脂蛋白的抗氧化功能可能会受损。HDL蛋白质组和脂质组的结构和组成异常是这种功能缺陷的基础。HDL颗粒（主要是小而致密的HDL 3）的代谢、循环水平、组成和生物活性的伴随正常化可以构成未来的治疗目标。LDL氧化显著增加LDL对巨噬细胞清道夫受体的亲和力，导致脂肪条纹形成。HDL颗粒，主要是小而致密的HDL 3，为LDL提供有效的保护，使其免受自由基的氧化损伤。HDL是一种多分子复合物，能够获得和灭活致动脉粥样硬化的氧化脂质。HDL的抗氧化功能在代谢疾病中受损; HDL功能的正常化可以是治疗目标。
Uptake of low-density lipoprotein (LDL) particles by macrophages represents a key step in the development of atherosclerotic plaques, leading to the foam cell formation. Chemical modification of LDL is however necessary to induce this process. Proatherogenic LDL modifications include aggregation, enzymatic digestion and oxidation. LDL oxidation by one-electron (free radicals) and two-electron oxidants dramatically increases LDL affinity to macrophage scavenger receptors, leading to rapid LDL uptake and fatty streak formation. Circulating high-density lipoprotein (HDL) particles, primarily small, dense, protein-rich HDL3, provide potent protection of LDL from oxidative damage by free radicals, resulting in the inhibition of the generation of pro-inflammatory oxidized lipids. HDL-mediated inactivation of lipid hydroperoxides involves their initial transfer from LDL to HDL and subsequent reduction to inactive hydroxides by redox-active Met residues of apolipoprotein A-I. Several HDL-associated enzymes are present at elevated concentrations in HDL3 relative to large, light HDL2 and can be involved in the inactivation of short-chain oxidized phospholipids. Therefore, HDL represents a multimolecular complex capable of acquiring and inactivating proatherogenic lipids. Antioxidative function of HDL can be impaired in several metabolic and inflammatory diseases. Structural and compositional anomalies in the HDL proteome and lipidome underlie such functional deficiency. Concomitant normalization of the metabolism, circulating levels, composition and biological activities of HDL particles, primarily those of small, dense HDL3, can constitute future therapeutic target. LDL oxidation dramatically increases LDL affinity to macrophage scavenger receptors, leading fatty streak formation. HDL particles, primarily small, dense HDL3, provide potent protection to LDL from oxidative damage by free radicals. HDL represents a multimolecular complex capable of acquiring and inactivating of proatherogenic oxidized lipids. Antioxidative function of HDL is impaired in metabolic diseases; normalization of HDL functions can be a therapeutic target.