Evaluation of phospholipid transfer protein and cholesteryl ester transfer protein as contributors to the generation of pre beta-high-density lipoproteins
High-density lipoproteins (HDLs) are considered anti-atherogenic because
they mediate peripheral cell cholesterol transport to the liver for
excretion and degradation. An important step in this reverse
cholesterol-transport pathway is the uptake of cellular cholesterol by a
specific subclass of small, lipid-poor apolipoprotein A-I particles
designated pre beta-HDL. The two lipid-transfer proteins present in human
plasma, cholesteryl ester transfer protein (CETP) and phospholipid
transfer protein (PLTP), have both been implicated in the formation of pre
beta-HDL. In order to investigate the relative contribution of each of
these proteins, we used transgenic mouse models. Comparisons were made
between human CETP transgenic mice (huCETPtg), human PLTP transgenic mice
(huPLTPtg) and mice transgenic for both lipid-transfer proteins
(huCETPtg/huPLTPtg). These animals showed elevated plasma levels of CETP
activity, PLTP activity or both activities, respectively. We evaluated the
generation of pre beta-HDL in mouse plasma by immunoblotting and crossed
immuno-electrophoresis. Generation of pre beta-HDL was equal in huCETPtg
and wild-type mice. In contrast, in huPLTPtg and huCETPtg/huPLTPtg mice,
pre beta-HDL generation was 3-fold higher than in plasma from either
wild-type or huCETPtg mice. Our findings demonstrate that, of the two
plasma lipid-transfer proteins, PLTP rather than CETP is responsible for
the generation of pre beta-HDL. These data support the hypothesis of a
role for PLTP in the initial stage of reverse cholesterol transport