Lu Fengyuan, Li En, Yang Xiaoyu
The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China.
School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
Front Pharmacol. 2024 Jul 30;15:1413123. doi: 10.3389/fphar.2024.1413123. eCollection 2024.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily secreted by hepatocytes. PCSK9 is critical in liver low-density lipoprotein receptors (LDLRs) metabolism. In addition to its hepatocellular presence, PCSK9 has also been detected in cardiac, cerebral, islet, renal, adipose, and other tissues. Once perceived primarily as a "harmful factor," PCSK9 has been a focal point for the targeted inhibition of both systemic circulation and localized tissues to treat diseases. However, PCSK9 also contributes to the maintenance of normal physiological functions in numerous extrahepatic tissues, encompassing both LDLR-dependent and -independent pathways. Consequently, PCSK9 deficiency may harm extrahepatic tissues in close association with several pathophysiological processes, such as lipid accumulation, mitochondrial impairment, insulin resistance, and abnormal neural differentiation. This review encapsulates the beneficial effects of PCSK9 on the physiological processes and potential disorders arising from PCSK9 deficiency in extrahepatic tissues. This review also provides a comprehensive analysis of the disparities between experimental and clinical research findings regarding the potential harm associated with PCSK9 deficiency. The aim is to improve the current understanding of the diverse effects of PCSK9 inhibition.
前蛋白转化酶枯草溶菌素/克新9型（PCSK9）主要由肝细胞分泌。PCSK9在肝脏低密度脂蛋白受体（LDLR）代谢中起关键作用。除了在肝细胞中存在外，PCSK9在心脏、大脑、胰岛、肾脏、脂肪及其他组织中也有检测到。PCSK9曾一度主要被视为“有害因子”，如今已成为通过靶向抑制全身循环和局部组织来治疗疾病的焦点。然而，PCSK9在许多肝外组织中对维持正常生理功能也有作用，包括依赖LDLR和不依赖LDLR的途径。因此，PCSK9缺乏可能与脂质蓄积、线粒体损伤、胰岛素抵抗及神经分化异常等多种病理生理过程密切相关，进而损害肝外组织。本综述总结了PCSK9对生理过程的有益作用以及PCSK9缺乏在肝外组织中引发的潜在疾病。本综述还全面分析了关于PCSK9缺乏潜在危害的实验研究结果与临床研究结果之间的差异。目的是增进目前对PCSK9抑制多种作用的理解。
