Abstract:

Elevated serum level of low density lipoprotein cholesterol (LDL-C) is the leading risk factor for cardiovascular disease. LDL receptor (LDLR)-mediated LDL clearance is the major factor determining the LDL-C level in the circulation. LDL binds to the LDLR on the cell surface and enters the cells through classical clathrin-coated vesicles. In the acidic endosome, LDLR is uncoupled from LDL and recycles back to the cell surface. The released LDL is transported to the lysosome for degradation. The proprotein convertase subtilisin kexin type 9 (PCSK9) gene encodes a hepatic secretory protein, and its mutations are strongly associated with levels of LDL-C. We and others have shown that PCSK9 directly interacts with LDLR on the cell surface and both are internalized through the clathrin-coated vesicles. However, in the acidic endosome, PCSK9 and LDLR form a tight complex and are targeted to lysosome for degradation, thereby reducing the level of LDLR on the surface of hepatocytes and decreasing hepatic clearance of LDL-C, which plays an important role in maintaining a relatively constant level of LDL in the plasma. Thus, blocking PCSK9 function has become a new strategy to treat hypercholesterolemia.In this review, we will summarize the latest progress in the functional and mechanistic studies of PCSK9 and also highlight the research progress of PCSK9 inhibitors. It aims to provide a reference for the study of PCSK9-LDLR pathway and the regulation of cholesterol metabolism.

Key words: LDL-C, LDL receptor, PCSK9, endocytosis, PCSK9 inhibitor