Abstract 110: Novel Apoc-II Mimetic Peptide Activates LPL and Decreases Serum Triglycerides in Mice.

Abstract

BACKGROUND Elevated triglycerides (TG) over 1000 mg/dL in patients with severe dyslipidemias can lead to pancreatitis. ApoA-I and its mimetic peptides, which are currently being explored as therapeutic agents for acute coronary syndrome, can also markedly increase serum TG. OBJECTIVE To examine the mechanism behind hypertriglyceridemia caused by apoA-I mimetic peptides and to develop novel peptides based on apoC-II for activating LPL and decreasing serum TG. METHODS The 18A-CII peptide was synthesized, using standard solid phase FMOC chemistry, and contains the 18A amphipathic helix (DWLKAFYDKVAEKLKEAF) linked to the last helix of apoC-II (AMSTYTGIFTDQVLSVLKGEE) with an intervening Pro residue. RESULTS High doses of the 5A apoA-I mimetic peptide (>120mg/kg) raised serum TG between 1000-1200mg/dL in non-fasting C57B/6 mice after a single bolus. By FPLC analysis, most of the TG were observed in VLDL. By in vitro lipolysis studies, 5A was found to be a direct inhibitor of LPL, whereas 18A-CII activated LPL. An inactive analogue of 18A-CII, containing 4 Ala substitutions for the residues (18A-P-AMSTATGAFTAAVLSVLKGEE) shown to bind to LPL, inhibited LPL activity. Intravenous injection of 30mg/kg of 18A-CII in C57BL/6 mice showed a 52% of reduction of LDL-C. In ApoE KO and LDLR KO mice, treatment with 18A-CII led to a marked TG reduction at 4 h of 85% and 53%, respectively, when compared to sham injected mice. Co-administration of 5A along with 18A-CII in mice still resulted in an increase in HDL-C observed with the 5A peptide but with no increase in serum TG. In order to test the effect of 18A-CII in humans, plasma from an ApoC-II deficient patient was treated with LPL. Addition of 18A-CII or apoC-II was similarly effective in restoring normal level of lipolysis after the addition of LPL. CONCLUSION In summary, 18A-CII is able to activate LPL both in vitro and in vivo and reduces serum TG levels and can overcome the inhibition of LPL observed with 5A. These results suggest that 18A-CII may be of value either in combination with an apoA-I mimetic peptide and or can be possibly be used to treat apoC-II deficiency.