Insights Into PCSK9, Low-Density Lipoprotein Receptor, and Low-Density Lipoprotein Cholesterol Metabolism

The identification of PCSK9 in 20031 has resulted in substantial revision to previous knowledge regarding cholesterol homeostasis, provided new insights into low-density lipoprotein (LDL) metabolism and LDL receptor (LDLR) function, and presented a new compelling therapeutic target to reduce LDL cholesterol (LDL-C). PCSK9 is a serine protease expressed predominantly in the liver, intestine, and kidney and regulates plasma LDL-C levels by binding to the epidermal growth factor A of the LDLR, targeting it for degradation rather than for recycling to the cell surface.2Article see p 2403Plasma levels of LDL-C and PCSK9 are related because overexpression or gain-of-function mutations of PCSK9 promote degradation of mainly hepatic LDLR, whereas loss-of-function mutations promote increased LDLR activity through enhanced recycling. The relationships between PCSK9, the LDLR, and plasma LDL-C have been the subject of intense study over the last decade, helped by transgenic mice models that can be made to express human PCSK9 and then studied in mice with and without LDLR defects. Although these studies have provided significant insights, the data have at times been inconsistent and confusing, particularly in 3 main areas that have potential clinical relevance: the role of PCSK9 in adrenal function, whether PCSK9 has an independent role in lipid metabolism other than via the LDLR, and the role of PCSK9 during statin therapy.In a series of elegant studies reported in this issue of Circulation , Tavori et al3 use these mouse models, supplemented with additional in vitro and in vivo experiments, to further elucidate the relationship between these parameters and provide some potential applications and extrapolations to human which may answer these questions and prove useful for current therapeutics in clinical development. The LDLR−/− mouse model provides a unique system in which to study the metabolism of both LDL and PCSK9 in …