HDL in the 21st Century: A Multifunctional Roadmap for Future HDL Research.
HDL in the 21st Century: A Multifunctional Roadmap for Future HDL Research.
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DOI：
10.1161/circulationaha.120.044221
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发表时间：
2021-06-08
期刊：
影响因子：
37.8
通讯作者：
Rye KA
中科院分区：
文献类型：
--
作者：
Rohatgi A;Westerterp M;von Eckardstein A;Remaley A;Rye KA
低高密度脂蛋白胆固醇（HDL-C）是动脉粥样硬化性血脂异常的特征，反映了不良的生活方式选择、代谢受损和心血管风险增加。低HDL-C也与炎症性疾病、恶性肿瘤、糖尿病和其他疾病的风险增加有关。这一流行病学证据尚未转化为提高HDL- c作为可行的治疗靶点，部分原因是HDL- c不能反映HDL的功能。孟德尔随机化分析没有发现HDL-C水平与心血管风险之间存在因果关系的证据，这进一步降低了将提高HDL-C水平作为治疗目标的兴趣。hdl由不同大小、电荷和组成的不同颗粒亚群组成，具有多种动态和环境依赖功能，特别是在急性和慢性炎症状态方面。这些功能包括逆向胆固醇运输，抑制炎症和氧化，以及抗糖尿病的特性。高密度脂蛋白具有抗炎作用，可以预防动脉粥样硬化和糖尿病，还具有促炎作用，可以帮助清除败血症中的病原体。此外，hdl的分子调控是复杂的，它与多种蛋白质、生物活性脂质和非编码rna相关。HDL生物标志物（HDL- c、HDL颗粒数和载脂蛋白A-I）的临床研究表明，HDL- c与心血管结局呈非线性关系，性别和种族的差异关系，以及冠状动脉与非冠状动脉事件的差异模式。新的HDL标记物也可能与心力衰竭、癌症和糖尿病有关。高密度脂蛋白功能标志物，即胆固醇外排能力，与冠状动脉疾病有关，但迄今仍是研究工具。最终，控制HDL代谢方面的治疗方法仍然是圣杯。迄今为止，没有一种药物被证明是成功的，但大多数药物针对的是HDL- c，而不是HDL功能的指标。未来的治疗策略应侧重于在患者病程的最佳时间优化其HDL功能。我们在这里提供了一个框架，以帮助研究和临床社区，以及资助机构和利益相关者，获得对这些主题的当前思考的见解，以及我们预测的HDLs研究和开发的令人兴奋的未来。
Low high density lipoprotein cholesterol (HDL-C) characterizes an atherogenic dyslipidemia that reflects adverse lifestyle choices, impaired metabolism, and increased cardiovascular risk. Low HDL-C is also associated with increased risk of inflammatory disorders, malignancy, diabetes, and other diseases. This epidemiologic evidence has not translated to raising HDL-C as a viable therapeutic target, partly because HDL-C does not reflect HDL function. Mendelian randomization analyses that have found no evidence of a causal relationship between HDL-C levels and cardiovascular risk have decreased interest in increasing HDL-C levels as a therapeutic target even further. HDLs comprise distinct subpopulations of particles of varying size, charge and composition that have several dynamic and context-dependent functions, especially with respect to acute and chronic inflammatory states. These functions include reverse cholesterol transport, inhibition of inflammation and oxidation, and anti-diabetic properties. HDLs can be anti-inflammatory, which may protect against atherosclerosis and diabetes, as well as pro-inflammatory, which may help clear pathogens in sepsis. In addition, the molecular regulation of HDLs is complex, as evidenced by their association with multiple proteins, as well as bioactive lipids and non-coding RNAs. Clinical investigations of HDL biomarkers (HDL-C, HDL particle number, and apolipoprotein A-I) have revealed non-linear relationships with cardiovascular outcomes, differential relationships by sex and ethnicity, and differential patterns with coronary versus non-coronary events. Novel HDL markers may also have relevance for heart failure, cancer, and diabetes. HDL function markers, namely cholesterol efflux capacity, are associated with coronary disease, but remain research tools thus far. Ultimately, therapeutics that manipulate aspects of HDL metabolism remain the holy grail. None thus far have proven to be successful, but most have targeted HDL-C, not metrics of HDL function. Future therapeutic strategies should focus on optimizing HDL function in the right patients at the optimal time in their disease course. We provide here a framework to help the research and clinical communities, as well as funding agencies and stakeholders, obtain insights into current thinking on these topics, and what we predict will be an exciting future for research and development on HDLs.