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

• Published in: The Journal of biological chemistry Vol. 272; no. 43; pp. 27393 - 27400
• Main Authors: Foger, B, Santamarina-Fojo, S, Shamburek, R.D, Parrot, C.L, Talley, G.D, Brewer, H.B. Jr
• Format: Journal Article
• Language: English
• Published: United States 24.10.1997
• Subjects: Adenoviridae; ADN; ANIMAL TRANSGENIQUE; ANIMALES TRANSGENICOS; Animals; Apolipoprotein A-I - biosynthesis; APOLIPOPROTEINS; APOPROTEINAS; APOPROTEINE; APOPROTEINS; BINDING PROTEINS; BLOOD CHEMISTRY; BLOOD COMPOSITION; BLOOD LIPIDS; BLOOD PLASMA; Carrier Proteins - biosynthesis; Carrier Proteins - blood; CHOLESTEROL; Cholesterol - blood; Cholesterol - metabolism; Cholesterol Esters - metabolism; Cholesterol, HDL - blood; COLESTEROL; COMPLEMENTARY DNA; COMPOSICION DE LA SANGRE; COMPOSITION DU SANG; DNA; ESTER; ESTERES; ESTERS; EXPRESION GENICA; EXPRESSION DES GENES; FOIE; FOSFOLIPIDOS; GENE EXPRESSION; Gene Expression Regulation; GENE TRANSFER; Gene Transfer Techniques; GENERO HUMANO; Genetic Vectors; GENRE HUMAIN; HEMOLIPIDOS; HIGADO; Humans; Kinetics; LECITHINE; LECITHINS; LECITINAS; LIPIDE SANGUIN; LIPOPROTEINAS; LIPOPROTEINE; LIPOPROTEINS; Lipoproteins, HDL - metabolism; LIVER; Liver - metabolism; Male; MANKIND; Membrane Proteins - biosynthesis; Membrane Proteins - blood; METABOLISME DES PROTEINES; METABOLISMO PROTEICO; MICE; Mice, Inbred C57BL; PHOSPHATIDE; PHOSPHATIDYLCHOLINES; Phosphatidylcholines - metabolism; Phospholipid Transfer Proteins; PHOSPHOLIPIDS; Phospholipids - metabolism; PLASMA SANGUIN; PLASMA SANGUINEO; PROTEIN METABOLISM; PROTEINAS AGLUTINANTES; PROTEINAS RECOMBINANTES; PROTEINE DE LIAISON; PROTEINE RECOMBINANTE; RATON; RECOMBINANT PROTEINS; Recombinant Proteins - biosynthesis; Recombinant Proteins - blood; SOURIS; TRANSFERENCIA DE GENES; TRANSFERT DE GENE; TRANSGENIC ANIMALS
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.272.43.27393

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 x 10(7) plaque-forming units (low dose) and 4 x 10(8) 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 micromol/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-beta-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.