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.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/1054 |
| Date | 06 1900 |
| Creators | Cole, Laura Kathleen |
| Contributors | Vance, Dennis E. (Biochemistry), Schultz, Michael C. (Biochemistry), Godbout, Rosaline (Oncology/Biochemistry), Dyck, Jason R. B. (Pediatrics/Pharmacology), Sul, Hei Sook (Nutritional Science and Toxicology, Univ of California, Berkeley, Vance, Dennis E. (Biochemistry) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 3132927 bytes, application/pdf |
| Relation | Cole, L.K., and Vance, D.E. (2010) The Journal of biological chemistry |
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