Lipoprotein lipase (LPL) is the major enzyme responsible for hydrolysis of triglyceride (TG) molecules present in circulating lipoproteins. LPL is thought to interact with circulating lipoproteins while bound to cell surface glycosaminoglycans on the luminal side of endothelial cells. By regulating the levels of TG-containing lipoproteins as well as HDL, LPL modulates factors which determine individual risk for atherogenesis. Recent data from our laboratory and other investigators have shown that in addition to its enzymatic role, LPL can also function as a ligand for lipoprotein uptake by cells. Studies which I performed showed that LPL increased uptake of low density lipoprotein (LDL) and lipid-emulsions by fibroblasts and THP-1 macrophages. Moreover, the LPL-lipoprotein complex appeared to be internalized by cell surface heparan sulfate proteoglycan and the low density lipoprotein receptor related protein but not by the LDL receptor. By testing the hypothesis that LPL would internalize retinyl ester (vitamin A) in the core of lipid emulsions, my colleagues and I discovered that LPL would hydrolyze retinyl ester into retinoid leading to increased retinoid uptake by adipocytes. The overall objective of the experiments in this application is to understand the varied physiological and pathophysiological roles of LPL. These include LPL actions which affect lipid and retinoid uptake and which modulate atherogenic processes. The application contains aims to confirm and quantify that previously reported in vitro actions of LPL do have similar effects in vivo. The experiments proposed will add to our understanding of factors that regulate blood lipid levels and cause dyslipidemias of patients with heart disease. In addition, they will test whether LPL affects how macrophages accumulate within blood vessels. Retinoids modulate differentiation of a number of cell types, e.g. into monocytes to macrophages and pre-adipocytes to adipocytes. Thus, our studies of vitamin A uptake by cells may be important for cellular events which affect overall body metabolism.
