Ajoolabady Amir, Pratico Domenico, Mazidi Mohsen, Davies Ian G, Lip Gregory Y H, Seidah Nabil, Libby Peter, Kroemer Guido, Ren Jun
Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Alzheimer's Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Metabolism. 2025 Feb;163:156064. doi: 10.1016/j.metabol.2024.156064. Epub 2024 Nov 14.
PCSK9 is a serine protease that regulates plasma levels of low-density lipoprotein (LDL) and cholesterol by mediating the endolysosomal degradation of LDL receptor (LDLR) in the liver. When PCSK9 functions unchecked, it leads to increased degradation of LDLR, resulting in elevated circulatory levels of LDL and cholesterol. This dysregulation contributes to lipid and cholesterol metabolism abnormalities, foam cell formation, and the development of various diseases, including cardiovascular disease (CVD), viral infections, cancer, and sepsis. Emerging clinical and experimental evidence highlights an imperative role for PCSK9 in metabolic anomalies such as hypercholesterolemia and hyperlipidemia, as well as inflammation, and disturbances in mitochondrial homeostasis. Moreover, metabolic hormones - including insulin, glucagon, adipokines, natriuretic peptides, and sex steroids - regulate the expression and circulatory levels of PCSK9, thus influencing cardiovascular and metabolic functions. In this comprehensive review, we aim to elucidate the regulatory role of PCSK9 in lipid and cholesterol metabolism, pathophysiology of diseases such as CVD, infections, cancer, and sepsis, as well as its pharmaceutical and non-pharmaceutical targeting for therapeutic management of these conditions.
前蛋白转化酶枯草溶菌素9（PCSK9）是一种丝氨酸蛋白酶，它通过介导肝脏中低密度脂蛋白受体（LDLR）的内溶酶体降解来调节血浆中低密度脂蛋白（LDL）和胆固醇的水平。当PCSK9不受控制地发挥作用时，会导致LDLR降解增加，从而使循环中的LDL和胆固醇水平升高。这种调节异常会导致脂质和胆固醇代谢异常、泡沫细胞形成以及包括心血管疾病（CVD）、病毒感染、癌症和脓毒症在内的各种疾病的发展。新出现的临床和实验证据突出了PCSK9在高胆固醇血症和高脂血症等代谢异常以及炎症和线粒体稳态紊乱中的重要作用。此外，代谢激素——包括胰岛素、胰高血糖素、脂肪因子、利钠肽和性类固醇——调节PCSK9的表达和循环水平，从而影响心血管和代谢功能。在这篇全面的综述中，我们旨在阐明PCSK9在脂质和胆固醇代谢中的调节作用、CVD、感染、癌症和脓毒症等疾病的病理生理学，以及针对这些病症进行治疗管理的药物和非药物靶向治疗。
