LAUSR

An apolipoprotein C-II peptide mimetic for the treatment of hypertriglyceridemia activates lipoprotein lipase and blocks apolipoprotein C-III. How low can you go? People with elevated plasma triglycerides face increased risk of cardiovascular disease. Wolska et al. developed a peptide, D6PV, that reduces triglycerides. D6PV mimics apolipoprotein C-II, a protein that makes up very low density lipoproteins and activates an enzyme that hydrolyzes triglycerides. D6PV promoted lipolysis in plasma from patients with hypertriglyceridemia and reduced triglycerides, low-density lipoproteins, and apolipoprotein C-III (an inhibitor of the enzyme that hydrolyzes triglycerides) in mouse models. The peptide also displayed good bioavailability in nonhuman primates, suggesting that it could be a potential treatment for hypertriglyceridemia. Recent genetic studies have established that hypertriglyceridemia (HTG) is causally related to cardiovascular disease, making it an active area for drug development. We describe a strategy for lowering triglycerides (TGs) with an apolipoprotein C-II (apoC-II) mimetic peptide called D6PV that activates lipoprotein lipase (LPL), the main plasma TG-hydrolyzing enzyme, and antagonizes the TG-raising effect of apoC-III. The design of D6PV was motivated by a combination of all-atom molecular dynamics simulation of apoC-II on the Anton 2 supercomputer, structural prediction programs, and biophysical techniques. Efficacy of D6PV was assessed ex vivo in human HTG plasma and was found to be more potent than full-length apoC-II in activating LPL. D6PV markedly lowered TG by more than 80% within a few hours in both apoC-II–deficient mice and hAPOC3-transgenic (Tg) mice. In hAPOC3-Tg mice, D6PV treatment reduced plasma apoC-III by 80% and apoB by 65%. Furthermore, low-density lipoprotein (LDL) cholesterol did not accumulate but rather was decreased by 10% when hAPOC3-Tg mice lacking the LDL-receptor (hAPOC3-Tg × Ldlr−/−) were treated with the peptide. D6PV lowered TG by 50% in whole-body inducible Lpl knockout (iLpl−/−) mice, confirming that it can also act independently of LPL. D6PV displayed good subcutaneous bioavailability of about 80% in nonhuman primates. Because it binds to high-density lipoproteins, which serve as a long-term reservoir, it also has an extended terminal half-life (42 to 50 hours) in nonhuman primates. In summary, D6PV decreases plasma TG by acting as a dual apoC-II mimetic and apoC-III antagonist, thereby demonstrating its potential as a treatment for HTG.