| Disruption of Uridine Homeostasis Links Liver Pyrimidine Metabolism to Lipid Accumulation. | |
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MedLine Citation:
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PMID: 23355744 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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We report in this study an intrinsic link between pyrimidine metabolism and liver lipid accumulation utilizing a uridine phosphorylase 1 transgenic mouse model UPase1-TG. Hepatic microvesicular steatosis is induced by disruption of uridine homeostasis through transgenic overexpression of UPase1, an enzyme of the pyrimidine catabolism and salvage pathway. Microvesicular steatosis is also induced by the inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme of the de novo pyrimidine biosynthesis pathway. Interestingly, uridine supplementation completely suppresses microvesicular steatosis in both scenarios. The effective concentration (EC50) for uridine to suppress microvesicular steatosis is approximately 20 uM in primary hepatocytes of UPase1-TG mice. We find that uridine does not have any effect on in vitro DHODH enzymatic activity. On the other hand, uridine supplementation alters the liver NAD+/NADH and NADP+/NADPH ratios and the acetylation profile of metabolic, oxidation-reduction, and antioxidation enzymes. Protein acetylation is emerging as a key regulatory mechanism for cellular metabolism. Therefore, we propose that uridine suppresses fatty liver by modulating liver protein acetylation profile. Our findings reveal a novel link between uridine homeostasis, pyrimidine metabolism, and liver lipid metabolism. |
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Authors:
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Thuc T Le; Amy Ziemba; Yasuyo Urasaki; Eugene Hayes; Steven Brotman; Giuseppe Pizzorno |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-24 |
Journal Detail:
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Title: Journal of lipid research Volume: - ISSN: 0022-2275 ISO Abbreviation: J. Lipid Res. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-28 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Desert Research Institute, United States; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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