Insights into PCSK9, LDL Receptor and LDL Cholesterol Metabolism: Of Mice and Man
The identification of PCSK9 in 20031 has resulted in substantial revision to prior knowledge regarding cholesterol homeostasis, provided new insights into LDL metabolism, 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 EGF-A of the LDLR targeting it for degradation rather than for recycling to the cell surface2.
Plasma levels of LDL-C and PCSK9 are related because over expression or gain-of-function mutations of PCSK9 promote degradation of mainly hepatic LDLR while 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. While these studies have provided significant insights, the data has been at times inconsistent and confusing, particularly in 3 main areas which have potential clinical relevance; the role of PCSK9 in adrenal function, if PCSK9 has an independent role in lipid metabolism other than via the LDLR, and the role of PCSK9 during statin therapy.
- Received May 10, 2013.
- Accepted May 13, 2013.