GPIHBP1, the Endothelial Cell Transporter for Lipoprotein Lipase
The discovery, by Drs. Beigneux, Fong, and Young, of severe chylomicronemia in GPIHBP1-deficient mice reignited interest in the lipolytic processing of triglyceride-rich lipoproteins. GPIHBP1 is a glycophosphidylinositol-anchored protein expressed exclusively in capillary endothelial cells, and it binds lipoprotein lipase (LPL) avidly. GPIHBP1 has two noteworthy protein domains, an amino-terminal acidic domain and a cysteine-rich Lymphocyte antigen 6 (Ly6) domain, and both are important for binding LPL. The localization of GPIHBP1 in capillaries, along with its ability to bind LPL, initially prompted speculation that GPIHBP1 served as an LPL binding site within the capillary lumen (creating “a platform for lipolysis”). More recent studies have identified a second and more intriguing role for GPIHBP1—picking up LPL in the subendothelial spaces (where it is secreted by myocytes and adipocytes) and then transporting it across endothelial cells to the capillary lumen, where it acts to hydrolyze the triglycerides within the plasma lipoproteins. Over the past few years, significant progress has been made in defining the amino acids within LPL and GPIHBP1 residues that are important for GPIHBP1–LPL interactions. Also, the human genetics of chylomicronemia has come into sharper focus. Some cases of chylomicronemia in humans are caused by mutant GPIHBP1 proteins that lack the ability to bind LPL, and others are caused by mutant LPL proteins that lack the ability to bind to GPIHBP1. The discovery of GPIHBP1 as the LPL transporter is a significant development in our understanding of lipoprotein physiology, and one that should lead to a vastly improved understanding of triglyceride metabolism and hyperlipidemia.
- © 2011 by American Heart Association, Inc.