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Volume 272, Number 43, Issue of October 24, 1997 pp. 27393-27400
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Plasma Phospholipid Transfer Protein
ADENOVIRUS-MEDIATED OVEREXPRESSION IN MICE LEADS TO DECREASED PLASMA HIGH DENSITY LIPOPROTEIN (HDL) AND ENHANCED HEPATIC UPTAKE OF PHOSPHOLIPIDS AND CHOLESTERYL ESTERS FROM HDL

(Received for publication, April 21, 1997, and in revised form, August 1, 1997)

From the Molecular Disease Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892

In vitro studies have shown that plasma phospholipid transfer protein (PLTP) converts isolated human high density lipoprotein-3 (HDL₃) into larger HDL particles and generates lipid-poor apoA-I containing nascent HDL. To evaluate the role of PLTP in vivo we generated recombinant adenovirus vectors containing either human PLTP cDNA (rPLTP.AdV) or the reporter luciferase cDNA as a control. After intravenous infusion of 4 × 10⁷ plaque-forming units (low dose) and 4 × 10⁸ plaque-forming units (high dose) of rPLTP.AdV into mice, PLTP activity in plasma increased from base-line levels of 8.4 ± 0.2 to 108 ± 17 and from 8.9 ± 0.6 to 352 ± 31 µmol/ml/h, respectively, on day 4 (both p < 0.001). Thus, both low and high doses of rPLTP.AdV led to pronounced overexpression of human PLTP in mice. On day 4 after treatment, mice treated with low and high doses of rPLTP.AdV showed decreased HDL cholesterol (54% and 91%) and apoA-I (64% and 98%) (all p < 0.05). Kinetic studies revealed that the fractional catabolic rates of HDL labeled with [³H]phosphatidylcholine, [¹⁴C]phosphatidylcholine ether, [³H]cholesteryl ether, and ¹²⁵I-labeled mouse apoA-I were increased by 8.5-, 8.7-, 3.8-, and 2.8-fold, respectively, in mice treated with low dose rPLTP.AdV (all p < 0.001). After injection of labeled HDL, mice treated with rPLTP.AdV showed an increased accumulation of labeled PC ether (+304%) and cholesteryl ether (+92%) in the liver (both p < 0.05). Two-dimensional gel electrophoresis of plasma 5 min after injection of HDL labeled with ¹²⁵I-apoA-I demonstrated increased levels of newly generated pre--HDL in mice overexpressing PLTP. In conclusion, HDL remodeling mediated by PLTP generates nascent, lipid-poor apoA-I in vivo and accelerates the hepatic uptake of HDL surface and core lipids in mice treated with rPLTP.AdV. Accelerated catabolism of HDL in mice overexpressing PLTP leads to low HDL levels. Our data indicate an important role for PLTP in modulating reverse cholesterol transport in vivo.

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