Lipids are a class of biomolecules that play an essential role in numerous biochemical functions, including energy production and homeostasis, cellular communication, and plasma membrane structure. However, lipids are also linked to many diseases and pathological processes, the most common of which are heart disease, diabetes, and inflammation. In order to maintain homeostasis, the body has an intricate and complex transport system to deliver cholesterol and fatty acid from the diet to vital tissues and organs, as well as a method to transport excess cholesterol from tissues and cells back to the liver where it can be excreted or recycled. Disruption or dysregulation in any parts of this system results in life-threatening diseases such as coronary artery disease. Utilizing a variety of biochemical, cell biology, and imaging approaches, we describe several recent findings in two important aspects of lipid metabolism—intravascular triglyceride metabolism and macrophage reverse cholesterol transport.
In the first several sections, studies describe the protein GPIHBP1. GPIHBP1 is a protein of capillary endothelial cells that is responsible for capturing lipoprotein lipase (LPL) and transporting it to the capillary lumen where LPL functions in hydrolysis of triglyceride-rich lipoproteins in the bloodstream, releasing fatty acids for use by surrounding tissues. Without GPIHBP1, LPL never reaches the capillary lumen and triglyceride hydrolysis is deficient, resulting in severe hypertriglyceridemia. In the following studies, we first developed and characterized several monoclonal antibodies (mAbs) against human GPIHBP1, then utilized these mAbs to better understand GPIHBP1’s role in hypercholesterolemia and cancer lipid metabolism.
In the later sections, we investigated macrophages and their role in reverse cholesterol transport. Macrophage have been known to internalize cholesterol and offload excess cholesterol back to the bloodstream and the liver. Cholesterol efflux from macrophages have been studied extensively and has generally been thought to involve direct transport of cholesterol from ATP-binding cassette (ABC) transporters to acceptors in the plasma such as high density lipoproteins (HDL). In these studies, we demonstrate that macrophages release ~20 to 100-nm particles derived from the plasma membrane and that these particles are highly enriched in a pool of accessible cholesterol. This release cholesterol-rich particles would greatly augment macrophages’ ability to offload excess cholesterol in reverse cholesterol transport.