Low density lipoproteins develop resistance to oxidative modification due to inhibition of cholesteryl ester transfer protein by a monoclonal antibody

Although numerous studies have investigated the relationship between choles teryl ester transfer protein (CETP) and high density lipoprotein (HDL) remo deling the relationship between CETP and low density Lipoproteins (LDL) is still not fully understood, In the present study, we examined the effect of the inhibition of CETP on both LDL oxidation and the uptake of the oxidize d LDL, which were made from LDL under condition of CETP inhibition, by macr ophages using a monoclonal antibody (mAb) to CETP in incubated plasma, The 6-h incubation of plasma derived from healthy fasting human subjects led to the transfer of cholesteryl ester (CE) from HDL to VLDL and LDL, and of tr iglycerides (TG) from VLDL to HDL and LDL, These net mass transfers of neut ral Lipids among the lipoproteins were eliminated by the mAb, The incubatio n of plasma either with or without the mAb did not affect the phospholipid compositions in any lipoproteins, As a result, the LDL fractionated from th e plasma incubated with the mAb contained significantly less CE and TG in c omparison to the LDL fractionated from the plasma incubated without the mAb , The percentage of fatty acid composition of LDL did not differ among the unincubated plasma, the plasma incubated with the mAb, and that incubated w ithout the mAb, When LDL were oxidized with CuSO4, the LDL Fractionated fro m the plasma incubated with the mAb were significantly resistant to die oxi dative modification determined by measuring the amount of TEARS and by cont inuously monitoring the formation of the conjugated dienes, in comparison t o the LDL fractionated from the plasma incubated without the mAb. The accum ulation of cholesteryl ester of oxidized LDL, which had been oxidized for 2 h with CuSO4, in J774.1 cells also decreased significantly in the LDL frac tionated from the plasma incubated with mAb in comparison to the LDL fracti onated from the plasma incubated without the mAb.jlr These results indicate that CETP inhibition reduces the composition of CE and TG in LDL and makes the LDL resistant to oxidation. In addition, the uptake of the oxidized LD L, which was made from the LDL under condition of CETP inhibition, by macro phages also decreased.