Abstract
Plasma phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) are homologous molecules that mediate neutral lipid and phospholipid exchange between plasma lipoproteins. Biochemical experiments suggest that only CETP can transfer neutral lipids but that there could be overlap in the ability of PLTP and CETP to transfer or exchange phospholipids. Recently developed PLTP gene knock-out (PLTP0) mice have complete deficiency of plasma phospholipid transfer activity and markedly reduced high density lipoprotein (HDL) levels. To see whether CETP can compensate for PLTP deficiency in vivo, we bred the CETP transgene (CETPTg) into the PLTP0 background. Using an in vivo assay to measure the transfer of [(3)H]PC from VLDL into HDL or an in vitro assay that determined [(3)H]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-apolipoprotein AI 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 versus 100 +/- 9, arbitrary units, respectively). Similar results were obtained on a high fat, high cholesterol diet. These results indicate 1) that there is no redundancy in function of PLTP and CETP in vivo and 2) that the combination of the CETP transgene with PLTP deficiency results in an additive lowering of HDL levels, suggesting that the phenotype of a human PLTP deficiency state would include reduced HDL levels.
Highlights
Cholesterol transport has been elucidated by human genetic deficiency of cholesteryl ester transfer protein (CETP) [2,3,4], as well as by the introduction of CETP, normally absent from mouse plasma, into mice by transgenesis [5,6,7,8]
Similar results were obtained on a high fat, high cholesterol diet. These results indicate 1) that there is no redundancy in function of phospholipid transfer protein (PLTP) and CETP in vivo and 2) that the combination of the CETP transgene with PLTP deficiency results in an additive lowering of high density lipoprotein (HDL) levels, suggesting that the phenotype of a human PLTP deficiency state would include reduced HDL levels
PLTP enhances net transfer of phospholipids from phosphatidylcholine (PC) vesicles into HDL, whereas CETP does not [10, 11]. This is thought to be analogous to the transfer of very low density lipoprotein (VLDL) phospholipids into HDL, but the ability of CETP to transfer phospholipids from VLDL into HDL has never been tested in vivo
Summary
Cholesterol transport has been elucidated by human genetic deficiency of CETP [2,3,4], as well as by the introduction of CETP, normally absent from mouse plasma, into mice by transgenesis [5,6,7,8]. Biochemical experiments indicate that PLTP and CETP have different abilities to transfer neutral lipids between lipoproteins, they suggest overlap in their ability to transfer or exchange phospholipids. Both lipid transfer proteins have been reported to facilitate phospholipid exchange between the plasma lipoproteins [10, 11]. PLTP enhances net transfer of phospholipids from phosphatidylcholine (PC) vesicles into HDL, whereas CETP does not [10, 11] This is thought to be analogous to the transfer of very low density lipoprotein (VLDL) phospholipids into HDL, but the ability of CETP to transfer phospholipids from VLDL into HDL has never been tested in vivo. If there is redundancy of phospholipid transfer activities, CETP would be expected to ameliorate the low HDL state of PLTP deficiency
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