Humans carrying ANGPTL3 loss-of-function mutations have reduced plasma TG (triglyceride), LDL-C (lowdensity lipoprotein cholesterol), and HDL-C (high-density lipoprotein cholesterol) levels. Antibody-mediated inhibition of ANGPTL-3 reduces TG, LDL-C, and HDL-C in mice, 2 monkeys, 2 and humans. 3 ANGPTL-3 inhibits LPL (lipoprotein lipase) and EL (endothelial lipase). The TG-and HDL-C-lowering effects of ANGPTL-3 inhibition are due to increased LPL and EL activity, respectively2; however, the mechanism for lowering LDL-C remains a mystery. It appears to be independent of the LDLR (LDL receptor), as ANGPTL-3 inhibition reduces LDL-C in Ldlr knockout mice4 and patients with homozygous familial hypercholesterolemia. 3

We previously reported that hepatic overexpression of EL in hypercholesterolemic mice reduced non-HDL-C, LDL-C, and apoB levels, 5 suggesting that increased EL activity as a result of ANGPTL-3 inhibition could contribute to the LDL-C reduction. In this report, we tested the dependence of LDL-C reduction upon Angptl3 silencing on EL by using mice lacking EL (EL-knockout). Because wild-type (WT) and EL-knockout mice have extremely low LDL-C levels, we raised LDL-C by using a siRNA to silence the hepatic Ldlr. Then, we administered an Angptl3 siRNA or a control siRNA and compared the changes in plasma lipid levels in WT and EL-knockout mice.