Research on Hepatocyte Regulation of PCSK9-LDLR and Its Related Drug Targets

The prevalence of hyperlipidemia has increased significantly due to genetic, dietary, nutritional and pharmacological factors, and has become one of the most common pathological conditions in humans. Hyperlipidemia can lead to a range of diseases such as atherosclerosis, stroke, coronary heart disease, myocardial infarction, diabetes, and kidney failure, etc. High circulating low-density lipoprotein cholesterol (LDL-C) is one of the causes of hyperlipidemia. LDL-C in the blood binds to LDL receptor (LDLR) and regulates cholesterol homeostasis through endocytosis. In contrast, proprotein convertase subtilisin/kexin type 9 (PCSK9) mediates LDLR degradation via the intracellular and extracellular pathways, leading to hyperlipidemia. Targeting PCSK9-synthesizing transcription factors and downstream molecules are important for development of new lipid-lowering drugs. Clinical trials regarding PCSK9 inhibitors have demonstrated a reduction in atherosclerotic cardiovascular disease events. The purpose of this review was to explore the target and mechanism of intracellular and extracellular pathways in degradation of LDLR and related drugs by PCSK9 in order to open up a new pathway for the development of new lipid-lowering drugs.

Automated summary

The prevalence of hyperlipidemia has increased significantly due to various factors and has become a common pathological condition. High circulating LDL-C is one of the causes of hyperlipidemia. LDL-C regulates cholesterol homeostasis through binding to LDLR, while PCSK9 mediates LDLR degradation, leading to hyperlipidemia. Targeting PCSK9-synthesizing transcription factors and downstream molecules is important for developing new lipid-lowering drugs.