The Jackson Laboratory, Bar Harbor, ME, USA.
Biomark Res. 2013 Sep 18;1(1):27. doi: 10.1186/2050-7771-1-27.
The proprotein convertase subtilisin/kexins (PCSKs) are a serine endopeptidase family. PCSK members cleave amino acid residues and modulate the activity of precursor proteins. Evidence from patients and animal models carrying genetic alterations in PCSK members show that PCSK members are involved in various metabolic processes. These studies further revealed the molecular mechanism by which genetic alteration of some PCSK members impairs normal molecular and physiological functions, which in turn lead to cardiovascular disease. High-density lipoprotein (HDL) is anti-atherogenic as it removes excessive amount of cholesterol from blood and peripheral tissues. Several PCSK members are involved in HDL metabolism. PCSK3, PCSK5, and PCSK6 process two triglyceride lipase family members, endothelial lipase and lipoprotein lipase, which are important for HDL remodeling. Recent studies in our lab found evidence that PCSK1 and PCSK9 are also involved in HDL metabolism. A mouse model carrying an amino acid substitution in PCSK1 showed an increase in serum apolipoprotein A1 (APOA1) level. Another mouse model lacking PCSK9 showed a decrease in APOE-containing HDL. In this review, we summarize the role of the five PCSK members in lipid, glucose, and bile acid (BA) metabolism, each of which can influence HDL metabolism. We propose an integrative model in which PCSK members regulate HDL metabolism through various molecular mechanisms and metabolic processes and genetic variation in some PCSK members may affect the efficiency of reverse cholesterol transport. PCSK members are considered as attractive therapeutic targets. A greater understanding of the molecular and physiological functions of PCSK members will improve therapeutic strategies and drug efficacy for cardiovascular disease where PCSK members play critical role, with fewer adverse effects.
脯氨酸内切蛋白酶枯草溶菌素/克氏蛋白酶（PCSKs）是丝氨酸内肽酶家族。PCSK 成员切割氨基酸残基并调节前体蛋白的活性。来自携带 PCSK 成员遗传改变的患者和动物模型的证据表明，PCSK 成员参与各种代谢过程。这些研究进一步揭示了某些 PCSK 成员的遗传改变如何损害正常的分子和生理功能，从而导致心血管疾病的分子机制。高密度脂蛋白（HDL）具有抗动脉粥样硬化作用，因为它可以从血液和外周组织中去除过多的胆固醇。几种 PCSK 成员参与 HDL 代谢。PCSK3、PCSK5 和 PCSK6 处理两种甘油三酯脂肪酶家族成员，内皮脂肪酶和脂蛋白脂肪酶，这对于 HDL 重塑很重要。我们实验室最近的研究发现证据表明，PCSK1 和 PCSK9 也参与了 HDL 代谢。携带 PCSK1 氨基酸取代的小鼠模型显示血清载脂蛋白 A1（APOA1）水平升高。另一种缺乏 PCSK9 的小鼠模型显示载脂蛋白 E 含有的 HDL 减少。在这篇综述中，我们总结了五个 PCSK 成员在脂质、葡萄糖和胆汁酸（BA）代谢中的作用，它们每一个都可以影响 HDL 代谢。我们提出了一个综合模型，其中 PCSK 成员通过各种分子机制和代谢过程调节 HDL 代谢，而某些 PCSK 成员的遗传变异可能会影响胆固醇逆向转运的效率。PCSK 成员被认为是有吸引力的治疗靶点。对 PCSK 成员的分子和生理功能有更深入的了解将改善治疗策略和药物疗效，从而改善心血管疾病的疗效，因为 PCSK 成员在其中发挥关键作用，并且副作用更少。
