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Permanent link (DOI): https://doi.org/10.7939/R3ZX5R

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Insights into the Transcriptional Regulation and Physiological Importance of Phosphatidylethanolamine N-Methyltransferase Open Access

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Other title
Subject/Keyword
Tamoxifen
Sp1
Phosphatidylcholine
Cardiac Dysfunction
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Cole, Laura Kathleen
Supervisor and department
Vance, Dennis E. (Biochemistry)
Examining committee member and department
Godbout, Rosaline (Oncology/Biochemistry)
Dyck, Jason R. B. (Pediatrics/Pharmacology)
Schultz, Michael C. (Biochemistry)
Sul, Hei Sook (Nutritional Science and Toxicology, Univ of California, Berkeley
Vance, Dennis E. (Biochemistry)
Department
Department of Biochemistry
Specialization

Date accepted
2010-04-07T19:56:48Z
Graduation date
2010-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Phosphatidylcholine (PC) is made in all nucleated mammalian cells via the CDP-choline pathway. Another major pathway for PC biosynthesis in liver is catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT). We have identified 3T3-L1 adipocytes as a cell culture model that expresses PEMT endogenously. Analysis of the proximal PEMT promoter in 3T3-L1 adipocytes revealed an important regulatory region. Sp1 binds to a GC-rich site within this section of the promoter and inhibits PEMT transcriptional activity. Tamoxifen is an anti-estrogen drug widely used for the treatment of hormone-responsive breast cancer but has a frequent side-effect of increasing accumulation of lipid in the liver (hepatic steatosis). Tamoxifen represses PEMT gene expression by promoting Sp1 binding to the promoter. However, decreased catalytic activity of PEMT was not a major initial contributor to tamoxifen-mediated hepatic steatosis. We found that increased de novo fatty acid synthesis is the primary event which leads to tamoxifen-induced steatosis in mouse liver. Tamoxifen did not significantly alter hepatic fatty acid uptake, triacylglycerol secretion or fatty acid oxidation. Finally, we provide evidence that deletion of the PEMT gene in a well-established mouse model of atherosclerosis (apolipoprotein E deficient) reduces the formation of aortic lesions and prevents the associated development of dilated cardiomyopathy. This beneficial effect is likely due a reduction of atherogenic lipoproteins. These results indicate that treatment strategies aimed at the inhibition of PEMT could prevent the development of atherosclerosis that predisposes individuals to heart failure.
Language
English
DOI
doi:10.7939/R3ZX5R
Rights
License granted by Laura Cole (lcole@ualberta.ca) on 2010-04-07T16:34:39Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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