Our lab studies the role of endothelial cells in lipid metabolism. The lipolytic processing of triglyceride-rich lipoproteins in the bloodstream by lipoprotein lipase (LPL) is the central event in plasma lipid metabolism. Acting inside capillaries, LPL cleaves lipoprotein triglycerides, releasing fatty acids that are taken up by tissues and either used for fuel or stored in cytosolic lipid droplets. LPL is synthesized by parenchymal cells (e.g. myocytes and adipocytes) and secreted into the interstitial spaces, but to be functional in processing triglycerides in the plasma, it must be transported to the capillary lumen. The endothelial cell protein GPIHBP1 serves as the LPL transporter, capturing LPL and moving it across endothelial cells to the capillary lumen. When GPIHBP1 is absent, LPL cannot reach the capillary lumen, leading to severe hypertriglyceridemia (in both humans and mice).
The identification of GPIHBP1 as the LPL transporter provided novel evidence that endothelial cells play an active role in plasma lipid metabolism. Maintaining metabolic homeostasis requires moving nutrients, hormones, and enzymes across capillary endothelial cells. Yet, how endothelial cell function is controlled so that metabolic activity inside capillaries and the delivery of nutrients across endothelial cells matches the needs of the underlying tissues has not been adequately explored. To address this issue, we study the mechanisms and regulation of trans-endothelial transport as it relates to lipid metabolism. We also study how the expression of capillary specific proteins, such as GPIHBP1, is controlled in an effort to learn how the metabolic needs of specific tissues influence gene expression in the capillaries servicing those tissues.
Figure 1. Lipoprotein lipase is synthesized and secreted by myocytes and adipocytes. Secreted LPL binds GPIHBP1 on the basolateral surface of endothelial cells and transported to the capillary lumen where LPL hydrolyzes the triglycerides of circulating lipoproteins.