| The development of a metabolic disease phenotype in CTP:phosphoethanolamine cytidylyltransferase-deficient mice. | |
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MedLine Citation:
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PMID: 19625253 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Phosphatidylethanolamine (PE) is an important inner membrane phospholipid mostly synthesized de novo via the PE-Kennedy pathway and by the decarboxylation of phosphatidylserine. CTP:phosphoethanolamine cytidylyltransferase (Pcyt2) catalyzes the formation of CDP-ethanolamine, which is often the rate regulatory step in the PE-Kennedy pathway. In the current investigation, we show that the reduced CDP-ethanolamine formation in Pcyt2(+/-) mice limits the rate of PE synthesis and increases the availability of diacylglycerol. This results in the increased formation of triglycerides, which is facilitated by stimulated de novo fatty acid synthesis and increased uptake of pre-existing fatty acids. Pcyt2(+/-) mice progressively accumulate more diacylglycerol and triglycerides with age and have modified fatty acid composition, predominantly in PE and triglycerides. Pcyt2(+/-) additionally have an inherent blockage in fatty acid utilization as energy substrate and develop impaired tolerance to glucose and insulin at an older age. Accordingly, gene expression analyses demonstrated the up-regulation of the main lipogenic genes and down-regulation of mitochondrial fatty acid beta-oxidation genes. These data demonstrate for the first time that to preserve membrane PE phospholipids, Pcyt2 deficiency generates compensatory changes in triglyceride and energy substrate metabolism, resulting in a progressive development of liver steatosis, hypertriglyceridemia, obesity, and insulin resistance, the main features of the metabolic syndrome. |
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Authors:
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Morgan D Fullerton; Fatima Hakimuddin; Arend Bonen; Marica Bakovic |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-07-22 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 284 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2009 Sep |
Date Detail:
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Created Date: 2009-09-14 Completed Date: 2009-10-19 Revised Date: 2010-09-21 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 25704-13 Citation Subset: IM |
Affiliation:
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Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cytidine Diphosphate / analogs & derivatives*, genetics, metabolism Diglycerides / genetics, metabolism Ethanolamines / metabolism* Fatty Liver / enzymology, genetics Female Gene Expression Regulation / genetics Hypertriglyceridemia / enzymology, genetics Insulin Resistance / genetics Lipid Metabolism, Inborn Errors / enzymology*, genetics Male Metabolic Syndrome X / enzymology, genetics Mice Mice, Knockout Phosphatidylethanolamines / biosynthesis*, genetics Phosphatidylserines / genetics, metabolism RNA Nucleotidyltransferases* Triglycerides / genetics, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Diglycerides; 0/Ethanolamines; 0/Phosphatidylethanolamines; 0/Phosphatidylserines; 0/Triglycerides; 3036-18-8/CDP ethanolamine; 39382-08-6/phosphatidylethanolamine; 63-38-7/Cytidine Diphosphate; EC 2.7.7.-/RNA Nucleotidyltransferases; EC 2.7.7.14/Ethanolamine-phosphate cytidylyltransferase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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