Chan Dick C, Ying Qidi, Watts Gerald F
Medical School, Faculty of Health and Medical Sciences, University of Western Australia.
Lipid Disorders Clinic, Department of Cardiology and Internal Medicine, Royal Perth Hospital, Perth, Western Australia, Australia.
Curr Opin Lipidol. 2021 Dec 1;32(6):378-385. doi: 10.1097/MOL.0000000000000795.
LDL, triglyceride-rich lipoprotein (TRL) and lipoprotein(a) [Lp(a)] particles are the key atherogenic lipoproteins. Deranged metabolism of these lipoproteins accounts for a spectrum of clinically important dyslipidemias, such as FH, elevated Lp(a) and diabetic dyslipidemia. We review the findings from recent dynamic and tracer studies that have contributed to expanding knowledge in this field.
Deficiency in LDL receptor activity does not only impair the catabolism of LDL-apoB-100 in FH, but also induces hepatic overproduction and decreases catabolism of TRLs. Patients with elevated Lp(a) are characterized by increased hepatic secretion of Lp(a) particles. Elevation of TRLs in diabetes is partly mediated by increased production of apoB-48 and apoC-III, and impaired clearance of apoB-48 in the postprandial state. Tracer kinetic studies show that proprotein convertase subtilisin/kexin type 9 mAbs alone or in combination with statin can increase the catabolism and decrease production of LDL and Lp(a) particles. By contrast, angiopoietin-like protein 3 inhibitors (e.g. evinacumab) reduce VLDL production and increase LDL clearance in FH. Glucagon-like peptide-1 receptor agonists can improve diabetic dyslipidemia by increasing the catabolism of apoB-48 and decreasing the production of apoB-48 and apoC-III.
Dynamic studies of the metabolism of atherogenic lipoproteins provide new insight into the nature of dyslipidemias and point to how new therapies with complementary modes of action may have maximal clinical impact.
低密度脂蛋白（LDL）、富含甘油三酯的脂蛋白（TRL）和脂蛋白(a) [Lp(a)]颗粒是主要的致动脉粥样硬化脂蛋白。这些脂蛋白的代谢紊乱导致了一系列临床上重要的血脂异常，如家族性高胆固醇血症（FH）、Lp(a)升高和糖尿病血脂异常。我们回顾了近期动态和示踪研究的结果，这些研究有助于扩展该领域的知识。
LDL受体活性缺乏不仅损害FH中LDL-载脂蛋白B-100（LDL-apoB-100）的分解代谢，还会诱导肝脏过度生成并降低TRL的分解代谢。Lp(a)升高的患者其特征是肝脏分泌Lp(a)颗粒增加。糖尿病患者TRL升高部分是由载脂蛋白B-48（apoB-48）和载脂蛋白C-III（apoC-III）生成增加以及餐后状态下apoB-48清除受损介导的。示踪动力学研究表明，前蛋白转化酶枯草溶菌素/kexin 9型单克隆抗体单独使用或与他汀类药物联合使用可增加LDL和Lp(a)颗粒的分解代谢并减少其生成。相比之下，血管生成素样蛋白3抑制剂（如evinacumab）可减少FH患者极低密度脂蛋白（VLDL）的生成并增加LDL清除。胰高血糖素样肽-1受体激动剂可通过增加apoB-48的分解代谢以及减少apoB-48和apoC-III的生成来改善糖尿病血脂异常。
对致动脉粥样硬化脂蛋白代谢的动态研究为血脂异常的本质提供了新的见解，并指出具有互补作用模式的新疗法如何可能产生最大的临床影响。
