Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Diabetes Obes Metab. 2021 Sep;23(9):2020-2034. doi: 10.1111/dom.14450. Epub 2021 Jun 17.
Atherosclerotic cardiovascular disease (ASCVD) is the largest cause of morbidity and mortality worldwide. Lipid-lowering therapies are the current major cornerstone of ASCVD management. Statins, ezetimibe, fibrates and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors effectively reduce the plasma low-density lipoprotein cholesterol (LDL-C) level in most individuals at risk of atherosclerosis. Still, some patients (such as those with homozygous familial hypercholesterolaemia), who do not respond to standard therapies, and other patients who cannot take these agents, remain at a high risk of ASCVD. In recent years there has been tremendous progress in understanding the mechanism and efficacy of lipid-lowering strategies. Apart from the recently approved PCSK9 and ATP citrate lyase inhibitors, angiopoietin-like 3 (ANGPTL3) is another potential target for the treatment of dyslipidaemia and its clinical sequalae of atherosclerosis. ANGPTL3 is a pivotal modulator of plasma triglycerides (TG), LDL-C and high-density lipoprotein cholesterol (HDL-C) levels, achieved by inhibiting the activities of lipoprotein lipase and endothelial lipase. Familial combined hypolipidaemia is derived from the Angptl3 loss-of-function mutations, which leads to low levels of LDL-C, HDL-C and TG, and has a 34% decreased risk of ASCVD compared with non-carriers. To date, monoclonal antibodies (evinacumab) and antisense oligonucleotides against ANGPTL3 have been investigated in clinical trials for dyslipidaemia therapy. Herein, we review the biology and function of ANGPTL3, as well as the latest developments of ANGPTL3-targeted therapies. We also summarize evidence from basic research to clinical trials, with the aim of providing novel insights into the biological functions of ANGPTL3 and related targeted therapies.
动脉粥样硬化性心血管疾病（ASCVD）是全球发病率和死亡率最高的疾病。降脂治疗是 ASCVD 管理的主要基石。他汀类药物、依折麦布、贝特类药物和前蛋白转化酶枯草溶菌素 9（PCSK9）抑制剂可有效降低大多数动脉粥样硬化风险患者的血浆低密度脂蛋白胆固醇（LDL-C）水平。然而，一些患者（如纯合子家族性高胆固醇血症患者）对标准治疗无反应，还有一些不能服用这些药物的患者，仍存在 ASCVD 的高风险。近年来，人们对降脂策略的机制和疗效有了深刻的认识。除了最近批准的 PCSK9 和三磷酸胞苷柠檬酸裂解酶抑制剂外，血管生成素样 3（ANGPTL3）也是治疗血脂异常及其 ASCVD 后果的另一个潜在靶点。ANGPTL3 是调节血浆甘油三酯（TG）、LDL-C 和高密度脂蛋白胆固醇（HDL-C）水平的关键调节剂，通过抑制脂蛋白脂肪酶和内皮脂肪酶的活性来实现。家族性混合型高脂血症是由于 Angptl3 功能丧失突变引起的，导致 LDL-C、HDL-C 和 TG 水平降低，与非携带者相比，ASCVD 风险降低 34%。迄今为止，针对 ANGPTL3 的单克隆抗体（evinacumab）和反义寡核苷酸已在降脂治疗的临床试验中进行了研究。在此，我们综述了 ANGPTL3 的生物学和功能，以及针对 ANGPTL3 的靶向治疗的最新进展。我们还总结了基础研究到临床试验的证据，旨在为 ANGPTL3 的生物学功能和相关靶向治疗提供新的见解。
