| 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. | |
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MedLine Citation:
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PMID: 19303980 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Marcelo J A Amar; Robert D Shamburek; Boris Vaisman; Catherine L Knapper; Bernhard Foger; Robert F Hoyt; Silvia Santamarina-Fojo; Hollis B Brewer; Alan T Remaley |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural |
Journal Detail:
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Title: Metabolism: clinical and experimental Volume: 58 ISSN: 1532-8600 ISO Abbreviation: Metab. Clin. Exp. Publication Date: 2009 Apr |
Date Detail:
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Created Date: 2009-03-23 Completed Date: 2009-04-20 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0375267 Medline TA: Metabolism Country: United States |
Other Details:
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Languages: eng Pagination: 568-75 Citation Subset: IM |
Affiliation:
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Lipoprotein Metabolism Section, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. mamar@mail.nih.gov |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenoviridae
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genetics* Animals Atherosclerosis / genetics* Chromatography, Liquid Humans Kinetics Lipoproteins, HDL / blood* Lipoproteins, LDL / blood* Male Phenotype Phosphatidylcholine-Sterol O-Acyltransferase / genetics*, metabolism Saimiri |
| Chemical | |
Reg. No./Substance:
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0/Lipoproteins, HDL; 0/Lipoproteins, LDL; EC 2.3.1.43/Phosphatidylcholine-Sterol O-Acyltransferase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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