Addressing dyslipidemic risk beyond LDL-cholesterol.
Addressing dyslipidemic risk beyond LDL-cholesterol.
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DOI：
10.1172/jci148559
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发表时间：
2022-01-04
期刊：
影响因子：
--
通讯作者：
Goldberg IJ
中科院分区：
文献类型：
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作者：
Tall AR;Thomas DG;Gonzalez-Cabodevilla AG;Goldberg IJ
尽管降低低密度脂蛋白的药物在减少心血管疾病(CVD)方面取得了成功，但仍有大量残留疾病的负担，部分原因是以富含甘油三酯的脂蛋白(TRL)水平升高和高密度脂蛋白(HDL)水平降低为特征的持续性血脂异常。由于肥胖和代谢综合征患病率上升，这种形式的血脂异常在全球范围内正在增加。越来越多的证据表明，肝脏对富含胆固醇的TRL残留物的清除障碍会导致它们在动脉中积聚，促进泡沫细胞的形成和炎症。低密度脂蛋白水平可能与泡沫细胞胆固醇外流减少有关，从而加重动脉粥样硬化。虽然贝特类和鱼油降低了TRL，但它们在减少心血管疾病方面并没有取得一致的成功，而且对减少残留和心血管疾病的新方法的需求还有很大的未得到满足。通过激活脂解来降低甘油三酯水平并与减少心血管疾病相关的罕见遗传变异为治疗血脂异常提供了新的方法。载脂蛋白C3(APOC3)和血管生成素样蛋白3(Angptl3)已成为抗体、反义或RNAi方法抑制的靶点。抑制任何一种分子都会降低TRL，但会分别升高或降低高密度脂蛋白水平。需要在具有高心血管风险和TRL水平升高的患者中进行此类药物的大型临床试验，以证明这些方法的有效性。
Despite the success of LDL-lowering drugs in reducing cardiovascular disease (CVD), there remains a large burden of residual disease due in part to persistent dyslipidemia characterized by elevated levels of triglyceride-rich lipoproteins (TRLs) and reduced levels of HDL. This form of dyslipidemia is increasing globally as a result of the rising prevalence of obesity and metabolic syndrome. Accumulating evidence suggests that impaired hepatic clearance of cholesterol-rich TRL remnants leads to their accumulation in arteries, promoting foam cell formation and inflammation. Low levels of HDL may associate with reduced cholesterol efflux from foam cells, aggravating atherosclerosis. While fibrates and fish oils reduce TRL, they have not been uniformly successful in reducing CVD, and there is a large unmet need for new approaches to reduce remnants and CVD. Rare genetic variants that lower triglyceride levels via activation of lipolysis and associate with reduced CVD suggest new approaches to treating dyslipidemia. Apolipoprotein C3 (APOC3) and angiopoietin-like 3 (ANGPTL3) have emerged as targets for inhibition by antibody, antisense, or RNAi approaches. Inhibition of either molecule lowers TRL but respectively raises or lowers HDL levels. Large clinical trials of such agents in patients with high CVD risk and elevated levels of TRL will be required to demonstrate efficacy of these approaches.