| Alteration of plasma HDL cholesteryl ester composition with transgenic expression of a point mutation (E149A) of human LCAT. | |
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MedLine Citation:
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PMID: 11590219 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have previously identified a single amino acid mutation (hE149A) in human LCAT that increases its in vitro reactivity with phosphatidylcholine species containing sn-2 arachidonate (Wang et al. 1997. J. Biol. Chem. 272: 280-286). The purpose of the present study was to determine whether in vivo overexpression of hE149A compared with human wild-type LCAT (hLCAT-wt) would be sufficient to enrich the steady state composition of plasma HDL cholesteryl esters (CE) with long chain (>18 carbon) polyunsaturated fatty acyl species. Transgenic lines with 20-fold overexpression of hLCAT were created and studied between 12 and 16 weeks of age while consuming a chow diet. Transgenic overexpression of hE149A compared with hLCAT-wt significantly enriched HDL with CE species containing 20:4 (45%) and 22:6 n-3 (108%), at the expense of those containing 18:2, without a significant change in the plasma HDL concentration, particle size, or phospholipid fatty acyl composition. Removing the contribution of endogenous mouse LCAT by crossing the transgenic mice into the mouse LCAT knockout background resulted in even greater changes in HDL CE composition, with a 2.4-, 5-, and 5-fold increase in 20:4, 20:5 n-3, and 22:6 n-3 cholesteryl esters in the hE149A mice compared with hLCAT-wt Tg mice, respectively. Our results demonstrate that in vivo expression of hE149A significantly enriches HDL cholesteryl esters in 20- and 22-carbon fatty acyl species without affecting HDL concentration or size. Furthermore, the data suggest that endogenous mouse LCAT in hLCAT transgenic mice contributes to the plasma HDL CE pool out of proportion to its mass, presumably because the hLCAT transgene is poorly activated by mouse apolipoprotein A-I. |
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Authors:
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J W Furbee; O Francone; J S Parks |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Journal of lipid research Volume: 42 ISSN: 0022-2275 ISO Abbreviation: J. Lipid Res. Publication Date: 2001 Oct |
Date Detail:
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Created Date: 2001-10-08 Completed Date: 2002-02-04 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: United States |
Other Details:
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Languages: eng Pagination: 1626-35 Citation Subset: IM |
Affiliation:
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Department of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1040, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Substitution
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genetics Animals Cholesterol Esters / blood, chemistry, metabolism* Chromatography, Gel Crosses, Genetic Fatty Acids, Unsaturated / analysis, blood Female Gene Expression Humans Lipids / blood Lipoproteins / blood, chemistry Lipoproteins, HDL / blood, chemistry, metabolism* Male Mice Mice, Knockout Mice, Transgenic Particle Size Phosphatidylcholine-Sterol O-Acyltransferase / blood, genetics*, metabolism* Point Mutation / genetics* Polymerase Chain Reaction |
| Grant Support | |
ID/Acronym/Agency:
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HL-07115/HL/NHLBI NIH HHS; HL-49373/HL/NHLBI NIH HHS; HL-54176/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cholesterol Esters; 0/Fatty Acids, Unsaturated; 0/HDL cholesteryl ester; 0/Lipids; 0/Lipoproteins; 0/Lipoproteins, HDL; 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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