Low levels of circulating high density lipoproteins (HDL) and high levels of plasma triglycerides (TG) are risk factors for cardiac disease and atherosclerosis. The liver-expressed protein angiopoietin-like 3 (ANGPTL3) regulates both plasma TG and HDL levels through inhibition of lipoprotein lipase (LPL), which hydrolyzes the triglycerides of TG-rich lipoproteins, and endothelial lipase (EL), which hydrolyzes the phospholipids of HDL. Recently ANGPTL8 has been shown to be essential for the ANGPTL3-mediated inhibition of LPL. However, the role of ANGPTL8 in modulating the inhibition of EL by ANGPTL3 (and thus modulating HDL levels) is not clear, nor has the mechanism by which ANGPTL3 inhibits LPL and EL been elucidated. In this thesis, I characterize the inhibition of EL by ANGPTL3 as most likely catalytic and show evidence that the ANGPTL proteins do not use cleavage as a mechanism to inhibit EL and LPL. I show that the presence of heparin partially blocks ANGPTL3 inhibition of EL and that EL bound to cells are protected from ANGPTL3 inhibition. I test ANGPTL3 mutants to provide information on how the protein structure alters its binding and inhibitory functions towards EL. Importantly, this thesis identifies that ANGPTL8 has no role in EL inhibition by ANGPTL3 and tests a common ANGPTL8 variant, R59W, to elucidate how LPL inhibition is altered. Finally, I characterize the activity of the T111I EL variant and found no differences in activity or ANGPTL3 inhibition of this mutant compared to wild-type. The contributions of this thesis increase our understanding of how ANGPTL3 and ANGTPL3+8 complexes regulate EL and LPL and modulate plasma lipoprotein levels and HDL. Understanding the mechanisms of ANGPTL3 inhibition of lipases and the role of ANGPTL8 in this inhibition, may advance efforts to pharmacologically target ANGPTL3 and ANGPTL8 to treat metabolic disorders caused by improper regulation and delivery of plasma lipids.