| Lecithin: cholesterol acyltransferase expression has minimal effects on macrophage reverse cholesterol transport in vivo. | |
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MedLine Citation:
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PMID: 19564558 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Lecithin:cholesterol acyltransferase (LCAT) catalyzes the formation of plasma cholesteryl ester, plays a key role in high-density lipoprotein metabolism, and has been believed to be critical in the process of reverse cholesterol transport (RCT). METHODS AND RESULTS: The role of LCAT in RCT from macrophages was quantified with a validated assay involving intraperitoneal injection in mice of (3)H-cholesterol-labeled J774 macrophages and monitoring the appearance of tracer in plasma, liver, bile, and feces. Human LCAT overexpression in human apolipoprotein A-I transgenic mice substantially increased plasma high-density lipoprotein cholesterol levels but surprisingly did not increase macrophage RCT. Even in the setting of coexpression of scavenger receptor BI or cholesteryl ester transfer protein, both of which promoted the transfer of LCAT-derived high-density lipoprotein cholesterol ester to the liver, LCAT overexpression still had no effect on RCT. Serum from LCAT-overexpressing mice had reduced ability to promote cholesterol efflux from macrophages ex vivo via ABCA1. To determine the effect of LCAT deficiency on macrophage RCT, LCAT(-/-) and LCAT(+/-) mice were compared with wild-type mice. Despite extremely low plasma levels of high-density lipoprotein cholesterol, LCAT-deficient mice had only a 50% reduction in RCT. LCAT(+/-) mice had normal RCT despite a significant reduction in high-density lipoprotein cholesterol. Serum from LCAT-deficient mice had increased ability to promote ABCA1-mediated cholesterol efflux from macrophages ex vivo. CONCLUSIONS: These results demonstrate that LCAT overexpression does not promote an increased rate of macrophage RCT. Although LCAT activity does become rate limiting in the context of complete LCAT deficiency, RCT is reduced by only 50% even in the absence of LCAT. These data suggest that macrophage RCT may not be as dependent on LCAT activity as has previously been believed. |
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Authors:
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Hiroyuki Tanigawa; Jeffrey T Billheimer; Jun-ichiro Tohyama; Ilia V Fuki; Dominic S Ng; George H Rothblat; Daniel J Rader |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-06-29 |
Journal Detail:
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Title: Circulation Volume: 120 ISSN: 1524-4539 ISO Abbreviation: Circulation Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-07-14 Completed Date: 2009-08-03 Revised Date: 2011-04-21 |
Medline Journal Info:
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Nlm Unique ID: 0147763 Medline TA: Circulation Country: United States |
Other Details:
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Languages: eng Pagination: 160-9 Citation Subset: AIM; IM |
Affiliation:
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Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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metabolism Animals Antigens, CD36 / metabolism Biological Transport / physiology Cell Line Cells, Cultured Cholesterol / metabolism* Cholesterol Ester Transfer Proteins / metabolism Cholesterol, HDL / metabolism Female Humans Injections, Intraperitoneal Macrophages / cytology, metabolism* Mice Mice, Knockout Mice, Transgenic Phosphatidylcholine-Sterol O-Acyltransferase / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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P01 HL022633-310006/HL/NHLBI NIH HHS; P01 HL059407-050003/HL/NHLBI NIH HHS; P01-HL22633/HL/NHLBI NIH HHS; P01-HL59407/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ATP binding cassette transporter 1; 0/ATP-Binding Cassette Transporters; 0/Antigens, CD36; 0/Cholesterol Ester Transfer Proteins; 0/Cholesterol, HDL; 57-88-5/Cholesterol; EC 2.3.1.43/Phosphatidylcholine-Sterol O-Acyltransferase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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