The lipolytic processing of triglyceride-rich lipoproteins (TRLs) is required for delivering lipid nutrients to vital tissues such as the heart. y Sponsor, Dr. Stephen Young, has focused on basic mechanisms of lipolysis. His group showed that GPIHBP1, a glycoprotein of capillary endothelial cells, is solely responsible for shuttling lipoprotein lipase (LPL) from the interstitial spaces to its site of action along the capillary lumn. They also showed that the LPL-GPIHBP1 complex is crucial for the margination of TRLs along capillaries (so that lipolysis can proceed). These discoveries were important; however, our understanding of lipolysis is far from being complete. For example, no one understands how the fatty acid products of lipolysis move across capillary endothelial cells to myocytes and adipocytes. It is unclear whether the fatty acids diffuse broadly along membrane surfaces; whether they traverse the endothelial cell cytoplasm; or whether they are shuttled across endothelial cells in transcytotic vesicles that contain CD36. Understanding how the products of lipolysis move across capillaries is highly relevant to cardiovascular disease-for several reasons. TRL processing by LPL is regulated by local concentrations of fatty acids, which likely depend on the efficiency of fatty acid transport across endothelial cells. Also, the efficiency of lipolysis regulates plasma triglyceride levels, which are an important factor in determining risk for coronary disease. Dr. Young has focused on mouse models, but examining TRL processing and lipid transport in other vertebrate species (e.g., birds, fish) is important. Other vertebrate species do not express GPIHBP1-the molecule that is so essential for LPL transport and TRL margination in mammals. Our preliminary studies suggest that the LPL in these species may not reach the capillary lumen. Understanding lipolysis and lipid transport in those species could yield insights into accessory mechanisms for lipid transport in mammals. The objective of my postdoctoral research program is to define mechanisms for fatty acid transport across capillaries. Lipid transport across capillaries has remained a black box, in large part because there was no way to visualize this process. Dr. Young's group has overcome that roadblock. They have used NanoSIMS imaging to produce high-resolution images of TRLs as they marginate along capillary endothelial cells. They found rare examples of intact TRLs traversing endothelial cells in vesicles, but the efforts to visualize free fatty acid movement were suboptimal because a large fraction of free fatty acids were lost during the preparation of tissue sections. I have surmounted that technical issue and am now positioned to use NanoSIMS imaging to visualize the movement of lipids across capillary endothelial cells. I will determine whether most fatty acids traverse endothelial cells in the very same vesicles that contain GPIHBP1, LPL, and CD36. Using mouse models, I will define the role of CD36 in capillary lipid transport. Finally, I will define LPL localization and lipid transport mechanisms in lower vertebrate species that do not express GPIHBP1.
My objective is to investigate the least understood topic within plasma triglyceride metabolism-mechanisms by which the fatty acid products of lipolysis move across capillary endothelial cells. An improved understanding of this topic will lead to a better understanding of both heart failure and atherosclerotic heart disease.
| He, Cuiwen; Weston, Thomas A; Jung, Rachel S et al. (2018) NanoSIMS Analysis of Intravascular Lipolysis and Lipid Movement across Capillaries and into Cardiomyocytes. Cell Metab 27:1055-1066.e3 |
| He, Cuiwen; Hu, Xuchen; Weston, Thomas A et al. (2018) Macrophages release plasma membrane-derived particles rich in accessible cholesterol. Proc Natl Acad Sci U S A 115:E8499-E8508 |
| He, Cuiwen; Hu, Xuchen; Jung, Rachel S et al. (2017) High-resolution imaging and quantification of plasma membrane cholesterol by NanoSIMS. Proc Natl Acad Sci U S A 114:2000-2005 |
| He, Cuiwen; Fong, Loren G; Young, Stephen G et al. (2017) NanoSIMS imaging: an approach for visualizing and quantifying lipids in cells and tissues. J Investig Med 65:669-672 |
| He, Cuiwen; Hu, Xuchen; Jung, Rachel S et al. (2017) Lipoprotein lipase reaches the capillary lumen in chickens despite an apparent absence of GPIHBP1. JCI Insight 2: |
