(A) APOC3 depletion via knockdown in the liver or antibody inhibition in the circulation reduces circulating TG levels via two mechanisms: (i) removal of APOC3 releases its inhibition of LPL and increases intravascular lipolysis, and (ii) loss of APOC3 promotes uptake of TRL in the liver. (B) ANGPTL3 depletion reduces TRLs and LDL via (i) reduced liver TG secretion; (ii) increased intravascular lipolysis; and increased hepatic removal via either (iii) LDLR-dependent, non–endothelial lipase–dependent or (iv) non–LDLR-dependent, endothelial lipase–dependent processes. HDL levels decrease with ANGPTL3 loss as a result of activation of endothelial lipase. EL, endothelial lipase; FFA, free fatty acid.