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The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis

Lookup NU author(s): John Petrie, Dr Gillian Patman, Ishita Sinha, Professor Helen ReevesORCiD, Professor Loranne Agius


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Plasma levels of uric acid, the final product of purine degradation in humans, are elevated in metabolic syndrome and are strongly associated with insulin resistance and nonalcoholic fatty liver disease (NAFLD). Hepatic and blood levels of purine metabolites (inosine, hypoxanthine, and xanthine) are also altered in pathophysiological states. We optimized a rat hepatocyte model to test the hypothesis that the production of uric acid by hepatocytes is a potential marker of compromised homeostasis of hepatocellular inorganic phosphate (P-i) and/or ATP. The basal rate of uric acid production from endogenous substrates in rat hepatocytes was comparable to that in human liver and was <10% of the maximum rate with saturating concentrations of purine substrates. It was marginally (similar to 20%) decreased by insulin and increased by glucagon but was stimulated more than twofold by substrates (fructose and glycerol) that lower both cell ATP and P-i, and by inhibitors of mitochondrial respiration (complexes I, III, and V) that lower ATP but raise cell P-i. Clearance of inosine and its degradation to uric acid were also inhibited by cell P-i depletion. Analysis of gene expression in NAFLD biopsies showed an association between mRNA expression of GCKR, the glucokinase regulatory protein that is functionally linked to uric acid production, and mRNA expression of the phosphate transporters encoded by SLC17A1/3. Uric acid production by hepatocytes is a very sensitive index of ATP depletion irrespective of whether cell P-i is lowered or raised. This suggests that raised plasma uric acid may be a marker of compromised hepatic ATP homeostasis.

Publication metadata

Author(s): Petrie JL, Patman GL, Sinha I, Alexander TD, Reeves HL, Agius L

Publication type: Article

Publication status: Published

Journal: American Journal of Physiology

Year: 2013

Volume: 305

Issue: 10

Pages: E1255-E1265

Print publication date: 15/11/2013

Acceptance date: 10/09/2013

ISSN (print): 0193-1849

ISSN (electronic): 1522-1555

Publisher: American Physiological Society


DOI: 10.1152/ajpendo.00214.2013


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Funder referenceFunder name
BDA 11/0004231Diabetes UK
G0501543Medical Research Council
HEALTH-F2-2009-241762European Community