Cholesteryl ester transfer protein and phospholipid transfer protein have nonoverlapping functions in vivo

Plasma phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) are homologous molecules that mediate neutral lipid and phos pholipid exchange between plasma lipoproteins, Biochemical experiments sugg est that only CETP can transfer neutral lipids but that there could be over lap in the ability of PLTP and CETP to transfer or exchange phospholipids. Recently developed PLTP gene knock-out (PLTP0) mice have complete deficienc y of plasma phospholipid transfer activity and markedly reduced high densit y lipoprotein (HDL) levels. To see whether CETP can compensate for PLTP def iciency in vivo, we bred the CETP transgene (CETPTg) into the PLTP0 backgro und. Using an in vivo assay to measure the transfer of [H-3]PC from VLDL in to HDL or an in vitro assay that determined [H-3]PC transfer from vesicles into HDL, we could detect no phospholipid transfer activity in either PLTP0 or CETPTg/PLTP0 mice. On a chow diet, HDL-PL, HDL-CE, and HDL-apolipoprote in Al in CETPTg/PLTP0 mice were significantly lower than in PLTP0 mice (45 +/- 7 versus 79 +/- 9 mg/dl; 9 +/- 2 versus 16 +/- 5 mg/dl; and 51 +/- 6 ve rsus 100 +/- 9, arbitrary units, respectively). Similar results were obtain ed on a high fat, high cholesterol diet. These results indicate 1) that the re is no redundancy in function of PLTP and CETP in vivo and 2) that the co mbination of the CETP transgene with PLTP deficiency results in an additive lowering of HDL levels, suggesting that the phenotype of a human PLTP defi ciency state would include reduced HDL levels.