Document Detail


Disruption of uridine homeostasis links liver pyrimidine metabolism to lipid accumulation.
MedLine Citation:
PMID:  23355744     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 (EC(50)) for uridine to suppress microvesicular steatosis is approximately 20 µM 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 the liver protein acetylation profile. Our findings reveal a novel link between uridine homeostasis, pyrimidine metabolism, and liver lipid metabolism.
Authors:
Thuc T Le; Amy Ziemba; Yasuyo Urasaki; Eugene Hayes; Steven Brotman; Giuseppe Pizzorno
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-24
Journal Detail:
Title:  Journal of lipid research     Volume:  54     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-21     Completed Date:  2013-09-30     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1044-57     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cells, Cultured
Fatty Acids / metabolism
Lipid Metabolism / drug effects
Liver / drug effects,  metabolism*
Male
Mice
Mice, Transgenic
Pyrimidines / metabolism*
Triglycerides / metabolism
Uridine / metabolism*
Uridine Phosphorylase / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
P20RR-016464/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Fatty Acids; 0/Pyrimidines; 0/Triglycerides; EC 2.4.2.3/Uridine Phosphorylase; K8CXK5Q32L/pyrimidine; WHI7HQ7H85/Uridine
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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