Ogura Masatsune
Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
J Cardiol. 2018 Jan;71(1):1-7. doi: 10.1016/j.jjcc.2017.07.002. Epub 2017 Aug 5.
Familial hypercholesterolemia (FH) is a frequent hereditary metabolic disease characterized by high serum low-density lipoprotein (LDL) cholesterol concentration and premature atherosclerotic cardiovascular disease (ASCVD). The discovery of the LDL receptor as one of the causative genes of FH enabled us to understand the pathophysiology of FH and paved the way for developing statins. Similar to LDL receptor, discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) also created an opportunity for developing its inhibitors. Since PCSK9 degrades LDL receptor protein, inhibiting PCSK9 will be an effective strategy. Evolocumab and alirocumab, anti-PCSK9 antibodies that inhibit binding between PCSK9 and LDL receptors, are now available in Japan. Adding an anti-PCSK9 antibody to standard therapy with statin alone or statin combined with ezetimibe further reduced serum LDL cholesterol levels by around 60% and they significantly decrease cardiovascular event incidence as compared with placebo. Additionally, the strong LDL cholesterol lowering effect of anti-PCSK9 antibody therapies has reportedly enabled the frequency of lipoprotein apheresis to be reduced or to be discontinued. As alternative strategies against PCSK9, antisense oligonucleotide agents that inhibit PCSK9 protein synthesis as well as a small interfering (or short interference) RNA (siRNA) for PCSK9 are also being developed. While relatively high cost can be given as a problem, PCSK9 inhibitors are able to reduce LDL cholesterol dramatically even in FH patients who could not achieve targets until now. To ensure that these drugs are given to the patients who really need them, it is necessary to raise the diagnosis rate and family screening has to be more actively conducted. Finally, it has been reported that PCSK9 is expressed not only in hepatocytes but also in other cells such as epithelial cells in small intestine and vascular smooth muscle cells in atherosclerotic plaque. Further research regarding extra-hepatic pathophysiology of PCSK9 is expected.
家族性高胆固醇血症（FH）是一种常见的遗传性代谢疾病，其特征是血清低密度脂蛋白（LDL）胆固醇浓度升高和早发性动脉粥样硬化性心血管疾病（ASCVD）。低密度脂蛋白受体作为FH的致病基因之一被发现，这使我们能够理解FH的病理生理学，并为他汀类药物的开发铺平了道路。与低密度脂蛋白受体类似，前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）的发现也为其抑制剂的开发创造了机会。由于PCSK9会降解低密度脂蛋白受体蛋白，抑制PCSK9将是一种有效的策略。依洛尤单抗和阿利西尤单抗是抑制PCSK9与低密度脂蛋白受体结合的抗PCSK9抗体，目前在日本已上市。在单独使用他汀类药物或他汀类药物与依折麦布联合的标准治疗中添加抗PCSK9抗体，可使血清LDL胆固醇水平进一步降低约60%，与安慰剂相比，它们显著降低了心血管事件发生率。此外，据报道，抗PCSK9抗体疗法强大的降低LDL胆固醇作用使脂蛋白分离术的频率得以降低或停止。作为针对PCSK9的替代策略，抑制PCSK9蛋白合成的反义寡核苷酸药物以及针对PCSK9的小干扰RNA（siRNA）也在研发中。虽然相对较高的成本可能是一个问题，但PCSK9抑制剂即使在目前尚未达到治疗目标的FH患者中也能显著降低LDL胆固醇。为确保这些药物用于真正需要的患者，有必要提高诊断率，必须更积极地开展家族筛查。最后，据报道，PCSK9不仅在肝细胞中表达，还在其他细胞中表达，如小肠上皮细胞和动脉粥样硬化斑块中的血管平滑肌细胞。预计将对PCSK9的肝外病理生理学进行进一步研究。
