Kontush Anatol, Chapman M John
Dyslipoproteinemia and Atherosclerosis Research Unit, National Institute for Health and Medical Research, Hôpital de la Pitié, 83 boulevard de l'Hôpital, 75651 Paris Cedex 13, France.
Pharmacol Rev. 2006 Sep;58(3):342-74. doi: 10.1124/pr.58.3.1.
High-density lipoproteins (HDL) possess key atheroprotective biological properties, including cellular cholesterol efflux capacity, and anti-oxidative and anti-inflammatory activities. Plasma HDL particles are highly heterogeneous in physicochemical properties, metabolism, and biological activity. Within the circulating HDL particle population, small, dense HDL particles display elevated cellular cholesterol efflux capacity, afford potent protection of atherogenic low-density lipoprotein against oxidative stress and attenuate inflammation. The antiatherogenic properties of HDL can, however be compromised in metabolic diseases associated with accelerated atherosclerosis. Indeed, metabolic syndrome and type 2 diabetes are characterized not only by elevated cardiovascular risk and by low HDL-cholesterol (HDL-C) levels but also by defective HDL function. Functional HDL deficiency is intimately associated with alterations in intravascular HDL metabolism and structure. Indeed, formation of HDL particles with attenuated antiatherogenic activity is mechanistically related to core lipid enrichment in triglycerides and cholesteryl ester depletion, altered apolipoprotein A-I (apoA-I) conformation, replacement of apoA-I by serum amyloid A, and covalent modification of HDL protein components by oxidation and glycation. Deficient HDL function and subnormal HDL-C levels may act synergistically to accelerate atherosclerosis in metabolic disease. Therapeutic normalization of attenuated antiatherogenic HDL function in terms of both particle number and quality of HDL particles is the target of innovative pharmacological approaches to HDL raising, including inhibition of cholesteryl ester transfer protein, enhanced lipidation of apoA-I with nicotinic acid and infusion of reconstituted HDL or apoA-I mimetics. A preferential increase in circulating concentrations of HDL particles possessing normalized antiatherogenic activity is therefore a promising therapeutic strategy for the treatment of common metabolic diseases featuring dyslipidemia, inflammation, and premature atherosclerosis.
高密度脂蛋白（HDL）具有关键的抗动脉粥样硬化生物学特性，包括细胞胆固醇流出能力以及抗氧化和抗炎活性。血浆HDL颗粒在物理化学性质、代谢和生物活性方面具有高度异质性。在循环的HDL颗粒群体中，小而致密的HDL颗粒表现出增强的细胞胆固醇流出能力，能有效保护致动脉粥样硬化的低密度脂蛋白免受氧化应激，并减轻炎症。然而，在与动脉粥样硬化加速相关的代谢疾病中，HDL的抗动脉粥样硬化特性可能会受到损害。事实上，代谢综合征和2型糖尿病不仅以心血管风险升高和HDL胆固醇（HDL-C）水平降低为特征，还以HDL功能缺陷为特征。功能性HDL缺乏与血管内HDL代谢和结构的改变密切相关。的确，具有减弱的抗动脉粥样硬化活性的HDL颗粒的形成在机制上与甘油三酯核心脂质富集、胆固醇酯消耗、载脂蛋白A-I（apoA-I）构象改变、血清淀粉样蛋白A取代apoA-I以及HDL蛋白成分通过氧化和糖基化进行共价修饰有关。HDL功能缺陷和HDL-C水平低于正常可能协同作用，加速代谢疾病中的动脉粥样硬化。在HDL颗粒数量和质量方面对减弱的抗动脉粥样硬化HDL功能进行治疗性正常化是提高HDL的创新药理学方法的目标，包括抑制胆固醇酯转移蛋白、用烟酸增强apoA-I的脂质化以及输注重组HDL或apoA-I模拟物。因此，优先增加具有正常抗动脉粥样硬化活性的HDL颗粒的循环浓度是治疗以血脂异常、炎症和过早动脉粥样硬化为特征的常见代谢疾病的一种有前景的治疗策略。
