School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia.
Department of Internal Medicine I, Regensburg University Hospital, 93053 Regensburg, Germany.
Int J Mol Sci. 2022 Jan 19;23(3):1070. doi: 10.3390/ijms23031070.
Chronic liver diseases are commonly associated with dysregulated cholesterol metabolism. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease of the proprotein convertase family that is mainly synthetized and secreted by the liver, and represents one of the key regulators of circulating low-density lipoprotein (LDL) cholesterol levels. Its ability to bind and induce LDL-receptor degradation, in particular in the liver, increases circulating LDL-cholesterol levels in the blood. Hence, inhibition of PCSK9 has become a very potent tool for the treatment of hypercholesterolemia. Besides PCSK9 limiting entry of LDL-derived cholesterol, affecting multiple cholesterol-related functions in cells, more recent studies have associated PCSK9 with various other cellular processes, including inflammation, fatty acid metabolism, cancerogenesis and visceral adiposity. It is increasingly becoming evident that additional roles for PCSK9 beyond cholesterol homeostasis are crucial for liver physiology in health and disease, often contributing to pathophysiology. This review will summarize studies analyzing circulating and hepatic PCSK9 levels in patients with chronic liver diseases. The factors affecting PCSK9 levels in the circulation and in hepatocytes, clinically relevant studies and the pathophysiological role of PCSK9 in chronic liver injury are discussed.
慢性肝脏疾病通常与胆固醇代谢失调有关。前蛋白转化酶枯草溶菌素 9（PCSK9）是一种丝氨酸蛋白酶，属于前蛋白转化酶家族，主要由肝脏合成和分泌，是调节循环中低密度脂蛋白（LDL）胆固醇水平的关键调节因子之一。其结合并诱导 LDL 受体降解的能力，特别是在肝脏中，增加了血液中循环 LDL-胆固醇的水平。因此，抑制 PCSK9 已成为治疗高胆固醇血症的一种非常有效的工具。除了 PCSK9 限制 LDL 衍生胆固醇的进入，影响细胞中的多种胆固醇相关功能外，最近的研究还将 PCSK9 与多种其他细胞过程相关联，包括炎症、脂肪酸代谢、癌症发生和内脏肥胖。越来越明显的是，除了胆固醇稳态之外，PCSK9 在健康和疾病中的其他作用对于肝脏生理学至关重要，通常有助于病理生理学。这篇综述将总结分析慢性肝脏疾病患者循环和肝组织中 PCSK9 水平的研究。讨论了影响循环和肝细胞中 PCSK9 水平的因素、临床相关研究以及 PCSK9 在慢性肝损伤中的病理生理作用。
