Dual Control of Low-Density Lipoprotein Cholesterol Levels by ANGPTL3 and ANGPTL8

In Ldlr-/- mice, ANGPTL8 lowers plasma LDL-cholesterol by ~20% and requires endothelial lipase (EL) plus ANGPTL3, while maximal LPL inhibition needs ANGPTL3 cleavage.

• Why it matters: ANGPTL3 is a proven LDLR-independent target, but the distinct roles of its full-length and cleaved fragments—and how ANGPTL8 cooperates—remain unclear for next-generation therapies.
• What they did: Liver perfusion compared VLDL secretion in mice with and without A3, and Ldlr-/- mice expressing A3-WT, A3-FL, or A3-Nter with or without A8 were analyzed for plasma lipids, A3/A8 complexes, and lipase activities.
• The result: A8 alone lowered LDL-C by ~20% depending on both EL and A3, maximal LPL inhibition required A8 plus both A3-FL and A3-Nter, and optimal EL inhibition required A8 but not A3 cleavage.