Abstract 207: ApoC-II Mimetic Peptide Blunts Post-Prandial Hypertriglyceridemia in Mice

Abstract

Post-prandial hypertriglyceridemia is as an important CVD risk factor. We recently described an apoC-II mimetic peptide (18A-CII) that activates LPL and lowers plasma TG in apoC-II-KO mice. To investigate 18A-CII as a therapy for post-prandial hyperTG, we investigated its effect on several mouse models after a fat challenge test. After an oral gavage with vegetable oil (10 μL/gram), plasma TG increased by 3 h in C57BL/6 mice by at least 5-fold but when mice were injected 30 min before gavage with 18A-CII (1 μmoL/kg; IP or SQ), the post-prandial TG rise was almost completely blunted. Similar results were found in apoE-KO mice, indicating that the effect of 18A-CII is independent of apoE. 18A-CII did not appear to work at the level of TG absorption, because it also rapidly accelerated plasma clearance of TG after IP injection of 20% Intralipid. Addition of exogenous LPL to plasma samples collected after IP injection with Intralipid revealed that lipoprotein particles from mice treated with 18A-CII were better substrates for LPL. The rise in plasma TG after IP injection of Intralipid was only partially blocked by about 50% when mice were co-injected with the LPL inhibitor Triton WR1339, indicating that 18A-CII also works by an LPL-independent mechanism. Incubation of human plasma with exogenous 18A-CII at doses comparable to that achieved in vivo in mice showed that 18A-CII binds to all lipoproteins, including HDL and causes the displacement of apoC-I and apoC-III. Furthermore, the in vitro inhibition of LPL from the addition of exogenous apoC-III could be overcome by adding 18A-CII at a molar ratio of at least 1:10 compared to apoC-III. In summary, the18A-CII mimetic peptide at relatively low doses can accelerate the clearance of post-prandial TG after a fat load. It does so in part by activating LPL but also by relieving the inhibition of LPL by apoC-III and possibly by also blocking the other known LPL-independent effects of apoC-III and possibly apoC-I in delaying the post-prandial clearance of TG.