Submitted on March 28, 2008
Accepted on March 28, 2008
COMMENTARY: PCSK9 function and physiology
Andrew S. Peterson, Loren G. Fong, and Stephen G. Young
Department of Molecular Biology, Genentech, South San Francisco, CA 94080-4990
Corresponding Author: Peterson.Andrew{at}gene.com
Abstract PCSK9 has exploded onto center stage of plasma cholesterol metabolism, raising hopes for a new strategy to treat hypercholesterolemia. PCSK9 in a plasma protein that triggers increased degradation of the LDL receptor. Gain-of-function mutations in PCSK9 reduce LDL receptor levels in the liver, resulting in high levels of LDL cholesterol in the plasma and increased susceptibility to coronary heart disease. Loss-offunction mutations lead to higher levels of the LDL receptor, lower LDL cholesterol levels, and protection from coronary heart disease. Two papers in this issue of JLR exemplify the rapid pace of progress in understanding PCSK9 molecular interactions and physiology. Dr. Shilpa Pandit and coworkers from Merck Research Laboratories describe the functional basis for the hypercholesterolemia associated with gain-offunction missense mutations in PCSK9. Dr. Jay Horton’s group at UT-Southwestern describe the kinetics and metabolism of PCSK9 and the impact of PCSK9 on LDL receptors in the liver and adrenal gland.
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