title: Adenoviral expression of human lecithin-cholesterol acyltransferase in nonhuman primates leads to an antiatherogenic lipoprotein phenotype by increasing high-density lipoprotein and lowering low-density lipoprotein.
abstract: Lecithin-cholesterol acyltransferase (LCAT), a key enzyme in high-density lipoprotein (HDL) metabolism, has been proposed to have atheroprotective properties by promoting reverse cholesterol transport. Overexpression of LCAT in various animal models, however, has led to conflicting results on its overall effect on lipoproteins and atherosclerosis. In this study, the effect of overexpression of LCAT in nonhuman primates on lipoprotein metabolism is examined. Human LCAT was expressed with adenovirus in squirrel monkeys (n = 8), resulting on day 4 in a 22-fold increase of LCAT activity (257 +/- 23 vs 5618 +/- 799 nmol mL(-1) h(-1), P < .0001). At its peak, LCAT was found to nearly double the level of HDL cholesterol from baseline (113 +/- 7 vs 260 +/- 24 mg/dL, P < .01). High-density lipoprotein formed after treatment with the adenovirus was larger in size, as assessed by fast protein liquid chromatography (FPLC) analysis. By kinetic studies, it was determined that there was a decrease in apolipoprotein (Apo) A-I resident time (0.373 +/- 0.027 vs 0.685 +/- 0.045 d(-1), P < .0001) and almost a doubling in the ApoA-I synthetic rate (22 +/- 2 vs 41 +/- 3 mg kg(-1) d(-1), P < .0001), but no overall change in ApoA-I levels. In addition, increased expression of LCAT was associated with a 37% reduction of ApoB levels (12 +/- 1 vs 19 +/- 1 mg/dL, P < .05) due to increased low-density lipoprotein catabolism (fractional catabolic rate = 1.7 +/- 0.1 d(-1) in controls vs 4.2 +/- 0.3 d(-1) in LCAT-treated group, P < .05). In summary, overexpression of LCAT in nonhuman primates leads to an antiatherogenic lipoprotein profile by increasing HDL cholesterol and lowering ApoB, thus making LCAT a potential drug target for reducing atherosclerosis.
authors.affiliation: Lipoprotein Metabolism Section, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. mamar@mail.nih.gov
authors.forename: Marcelo J A
authors.initials: MJ
authors.lastname: Amar
authors.forename: Robert D
authors.initials: RD
authors.lastname: Shamburek
authors.forename: Boris
authors.initials: B
authors.lastname: Vaisman
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Knapper
authors.forename: Bernhard
authors.initials: B
authors.lastname: Foger
authors.forename: Robert F
authors.initials: RF
authors.lastname: Hoyt
authors.forename: Silvia
authors.initials: S
authors.lastname: Santamarina-Fojo
authors.forename: Hollis B
authors.initials: HB
authors.lastname: Brewer
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics*; D002853:Chromatography, Liquid; D006801:Humans; D007700:Kinetics; D008075:Lipoproteins, HDL / Q000097:blood*; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D010641:Phenotype; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics* / Q000378:metabolism; D012453:Saimiri
chemical_list: D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase