Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia.
Faculty of Medicine and Health, University of New England, Armidale, Australia.
Metabolism. 2021 Nov;124:154887. doi: 10.1016/j.metabol.2021.154887. Epub 2021 Sep 8.
Dysregulated lipoprotein metabolism is a major cause of atherosclerotic cardiovascular disease (ASCVD). Use of stable isotope tracers and compartmental modelling have provided deeper understanding of the mechanisms underlying lipid disorders in patients at high risk of ASCVD, including familial hypercholesterolemia (FH), elevated lipoprotein(a) [Lp(a)] and metabolic syndrome (MetS). In patients with FH, deficiency in low-density lipoprotein (LDL) receptor activity not only impairs the catabolism of LDL, but also induces hepatic overproduction and decreases catabolism of triglyceride-rich lipoproteins (TRLs). Patients with elevated Lp(a) are characterized by increased hepatic secretion of Lp(a) particles. Atherogenic dyslipidemia in MetS patients relates to a combination of overproduction of very-low density lipoprotein-apolipoprotein (apo) B-100, decreased catabolism of apoB-100-containing particles, and increased catabolism of high-density lipoprotein-apoA-I particles, as well as to impaired clearance of TRLs in the postprandial state. Kinetic studies show that weight loss, fish oils, statins and fibrates have complementary modes of action that correct atherogenic dyslipidemia. Defining the kinetic mechanisms of action of proprotein convertase subtilisin/kexin type 9 and angiopoietin-like 3 inhibitors on lipid and lipoprotein mechanism in dyslipidemic subjects will further our understanding of these therapies in decreasing the development of ASCVD. "Everything changes but change itself. Everything flows and nothing remains the same... You cannot step twice into the same river, for other waters and yet others go flowing ever on." Heraclitus (c.535- c. 475 BCE).
脂蛋白代谢失调是动脉粥样硬化性心血管疾病（ASCVD）的主要病因。稳定同位素示踪剂和房室模型分析加深了我们对高危 ASCVD 患者脂质紊乱机制的理解，这些患者包括家族性高胆固醇血症（FH）、脂蛋白（a）[Lp(a)]升高和代谢综合征（MetS）。在 LDL 受体活性缺陷的 FH 患者中，不仅 LDL 的代谢被破坏，而且还会导致肝脏产生过多的脂蛋白并降低富含甘油三酯的脂蛋白（TRL）的代谢。Lp(a)升高的患者的特征是肝脏分泌更多的 Lp(a)颗粒。MetS 患者的致动脉粥样硬化性血脂异常与极低密度脂蛋白-载脂蛋白（apo）B-100 的过度产生、载脂蛋白 B-100 颗粒的代谢减少、高密度脂蛋白-apoA-I 颗粒的代谢增加以及餐后 TRL 清除受损有关。动力学研究表明，减肥、鱼油、他汀类药物和贝特类药物具有互补的作用机制，可纠正致动脉粥样硬化性血脂异常。确定前蛋白转化酶枯草溶菌素/激肽释放酶 9 和血管生成素样蛋白 3 抑制剂在血脂和脂蛋白机制方面对血脂异常患者的作用机制，将有助于我们了解这些疗法在降低 ASCVD 发展方面的作用。“万物皆变，不变者唯变。万物皆流，无物常住。人不能两次踏进同一条河流。”赫拉克利特（约公元前 535 年-公元前 475 年）。
