title: Lecithin:cholesterol acyltransferase overexpression generates hyperalpha-lipoproteinemia and a nonatherogenic lipoprotein pattern in transgenic rabbits.
abstract: Cholesterol esterification within plasma lipoprotein particles is catalyzed by lecithin:cholesterol acyltransferase (LCAT). The impact of the overexpression of this enzyme on plasma concentrations of the different plasma lipoproteins in an animal model expressing cholesteryl ester transfer protein was evaluated by generating rabbits expressing human LCAT. A 6.2-kilobase human genomic DNA construct was injected into the pronuclei of rabbit embryos. Of the 1002 embryos that were injected, 3 founder rabbits were characterized that expressed the human LCAT gene. As in mice and humans, the principal sites of mRNA expression in these rabbits is in the liver and brain, indicating that the regulatory elements required for tissue-specific expression among these species are similar. The alpha-LCAT activity correlated with the number of copies of LCAT that integrated into the rabbit DNA. Compared with controls, the high expressor LCAT-transgenic rabbits total and high density lipoprotein (HDL) cholesterol concentrations were increased 1.5-2.5-fold with a 3.1-fold increase in the plasma cholesterol esterification rate. Analysis of the plasma lipoproteins by fast protein liquid chromatography indicates that these changes reflected an increased concentration of apolipoprotein E-enriched, HDL1-sized particles, whereas atherogenic apolipoprotein B particles disappeared from the plasma. The concentrations of plasma HDL cholesterol were highly correlated with both human LCAT mass (r = 0.93; p = 0.001) and the log LCAT activity (r = 0.94; p < 0.001) in the transgenic rabbits. These results indicate that overexpression of LCAT in the presence of cholesteryl ester transfer protein leads to both hyperalpha-lipoproteinemia and reduced concentrations of atherogenic lipoproteins.
authors.affiliation: Molecular Disease Branch Laboratory of Animal Medicine and Surgery, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1666, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Hoeg
authors.forename: B L
authors.initials: BL
authors.lastname: Vaisman
authors.forename: S J
authors.initials: SJ
authors.lastname: Demosky
authors.forename: S M
authors.initials: SM
authors.lastname: Meyn
authors.forename: G D
authors.initials: GD
authors.lastname: Talley
authors.forename: R F
authors.initials: RF
authors.lastname: Hoyt
authors.forename: S
authors.initials: S
authors.lastname: Feldman
authors.forename: A M
authors.initials: AM
authors.lastname: Bérard
authors.forename: N
authors.initials: N
authors.lastname: Sakai
authors.forename: D
authors.initials: D
authors.lastname: Wood
authors.forename: M E
authors.initials: ME
authors.lastname: Brousseau
authors.forename: S
authors.initials: S
authors.lastname: Marcovina
authors.forename: H B
authors.initials: HB
authors.lastname: Brewer
authors.forename: S
authors.initials: S
authors.lastname: Santamarina-Fojo
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001053:Apolipoproteins / Q000097:blood*; D015152:Blotting, Northern; D001921:Brain / Q000201:enzymology; D002784:Cholesterol / Q000097:blood; D002788:Cholesterol Esters / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood*; D004622:Embryo, Mammalian; D005260:Female; D015870:Gene Expression; D006801:Humans; D006951:Hyperlipoproteinemias / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D009928:Organ Specificity; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010743:Phospholipids / Q000097:blood; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D011817:Rabbits; D012016:Reference Values; D014280:Triglycerides / Q000097:blood
chemical_list: D001053:Apolipoproteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D010743:Phospholipids; D012333:RNA, Messenger; D014280:Triglycerides; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase