| AAV8-Mediated Long-Term Expression of Human LCAT Significantly Improves Lipid Profiles in hCETP;Ldlr(+/-) Mice. | |
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MedLine Citation:
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PMID: 21822774 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Lecithin:cholesterol acyltransferase (LCAT) is the key circulating enzyme responsible for high-density lipoprotein (HDL) cholesterol esterification, HDL maturation, and potentially reverse cholesterol transport. To further explore LCAT's mechanism of action on lipoprotein metabolism, we employed adeno-associated viral vector (AAV) serotype 8 to achieve long-term (32-week) high level expression of human LCAT in hCETP;Ldlr(+/-) mice, and characterized the lipid profiles in detail. The mice had a marked increase in HDL cholesterol, HDL particle size, and significant reduction in low-density lipoprotein (LDL) cholesterol, plasma triglycerides, and plasma apoB. Plasma LCAT activity significantly increased with humanized substrate specificity. HDL cholesteryl esters increased in a fashion that fits human LCAT specificity. HDL phosphatidylcholines trended toward decrease, with no change observed for HDL lysophosphatidylcholines. Triglycerides reduction appeared to reside in all lipoprotein particles (very low-density lipoprotein (VLDL), LDL, and HDL), with HDL triglycerides composition highly reflective of VLDL, suggesting that changes in HDL triglycerides were primarily driven by the altered triglycerides metabolism in VLDL. In summary, in this human-like model for lipoprotein metabolism, AAV8-mediated overexpression of human LCAT resulted in profound changes in plasma lipid profiles. Detailed lipid analyses in the lipoprotein particles suggest that LCAT's beneficial effect on lipid metabolism includes not only enhanced HDL cholesterol esterification but also improved metabolism of apoB-containing particles and triglycerides. Our findings thus shed new light on LCAT's mechanism of action and lend support to its therapeutic potential in treating dyslipidemia. |
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Authors:
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Zhu Chen; Donald Chu; Jose M Castro-Perez; Weihua Ni; Aiwu Zhang; Mihajlo L Krsmanovic; Dan Xie; Vinit Shah; Steven J Stout; David G McLaren; Alice C Stefanni; Sang Ho Lee; Thomas P Roddy; Andrew S Plump; Brian K Hubbard; Thomas F Vogt; Heather H Zhou |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-8-6 |
Journal Detail:
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Title: Journal of cardiovascular translational research Volume: - ISSN: 1937-5395 ISO Abbreviation: - Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-8-8 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101468585 Medline TA: J Cardiovasc Transl Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Atherosclerosis, Cardiovascular Diseases, Merck Research Laboratories, RY80T-A100, 126 E. Lincoln Ave, Rahway, NJ, 07065, USA, zhu_chen@merck.com. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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