HDL Structure and Metabolism During Inflammation

炎症过程中 HDL 的结构和代谢

• 批准号: 7219726
• 负责人: FREDERICK C. DE BEER
• 金额: $ 32.69万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7219726
• 关键词: Acute; Adenovirus Vector; Affect; Animal Model; Apolipoproteins; Apolipoproteins A; Atherosclerosis; Binding; Blood Vessels; Catabolism; Charge; Cholesterol; Cholesterol Ester Transfer Proteins; Chronic; Deposition; Disease; Equilibrium; Generations; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Hydrolysis; Inflammation; Inflammatory; Label; Lipase; Lipids; Lipoproteins; Metabolic; Metabolism; Movement; Myocardial Infarction; Nature; Patients; Phase; Phospholipase; Phospholipids; Plasma; Process; Rate; Reaction; Research Personnel; Respiratory Tract Infections; Rheumatoid Arthritis; Serum amyloid A protein; Site; Stroke; Structure; Surface; Testing; Time; Tissues; Transgenic Mice; Validation; base; cytokine; hepatic lipase; human PLA2G2A protein; in vivo; metabolic abnormality assessment; particle; programs; size; uptake; urinary

Intimate associations exist between atherosclerosis and inflammation. The atherosclerotic process itself has features of chronic inflammation. Furthermore, the process of atherosclerosis is profoundly accelerated by chronic inflammatory disease states such as rheumatoid arthritis. Recently higher rates of first and subsequent myocardial infarctions, as well as strokes, were observed in patients with acute urinary and respiratory infections. Perhaps most notable amongst the plethora of metabolic changes that affect lipid and lipoproteins during inflammation are the structural and metabolic alterations of HDL. In practically all species there is a significant decrease of HDL cholesterol and apolipoprotein A-l (apoA-l). Serum amyloid A protein (SAA) is dramatically induced by cytokines and can even become the major apolipoprotein of HDL. The same cytokines concomitantly induce the inflammatory phospholipases particularly group MA secretory phospholipase A2 (group IIA sPLA2) that hydrolyze HDL surface phospholipids with significant metabolic sequelae. In the short term these changes are likely required for survival, but if chronically maintained could have long-term pathological consequences. The thesis of this proposal is that the acute phase phospholipases (group IIA sPLA2) act in concert with cholesterol ester transfer protein (CETP) to propel the apolipoproteins (SAA and apoA-l) associated with spherical HDL to distinct lipid-poor SAA or apoA-l entities (including prep HDL) and/or even "free" apolipoproteins. This process hold major implications for HDL function and metabolism during inflammation. Specifically, the lipid-poor apoA-l and SAA entities likely promote cholesterol efflux whilst at the same time being susceptible to accelerated catabolism.

动脉粥样硬化和炎症之间存在密切联系。动脉粥样硬化过程本身 慢性炎症的特征。此外，动脉粥样硬化的过程是深刻的加速， 慢性炎性疾病状态，如类风湿性关节炎。最近， 在急性泌尿系疾病患者中观察到随后的心肌梗死和中风， 呼吸道感染也许最值得注意的是过多的代谢变化，影响脂质和 炎症期间的脂蛋白是HDL的结构和代谢改变。在几乎所有物种中 HDL胆固醇和载脂蛋白A-1（apoA-1）显著降低。血清淀粉样蛋白a (SAA)在细胞因子的诱导下，其表达量显著增加，甚至可成为HDL的主要载脂蛋白。的 相同的细胞因子伴随诱导炎性磷脂酶，特别是MA组分泌 磷脂酶A2（IIA组sPLA 2）水解HDL表面磷脂，具有显著代谢 后遗症在短期内，这些变化可能是生存所必需的，但如果长期维持， 有长期的病理后果。 这一建议的论点是，急性期磷脂酶（IIA组sPLA 2）协同作用， 与胆固醇酯转移蛋白（CETP）一起推动载脂蛋白（SAA和apoA-I） 与球形HDL相关的不同的脂质贫乏SAA或apoA-I实体（包括制备型HDL） 和/或甚至“游离的”载脂蛋白。这一过程对HDL功能具有重要意义， 炎症过程中的代谢。具体地，脂质贫乏的apoA-I和SAA实体可能促进细胞凋亡。 胆固醇流出，同时易受加速催化剂的影响。