title: The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis.
abstract: 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 (Pi) 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 (~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 Pi, and by inhibitors of mitochondrial respiration (complexes I, III, and V) that lower ATP but raise cell Pi. Clearance of inosine and its degradation to uric acid were also inhibited by cell Pi 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 Pi is lowered or raised. This suggests that raised plasma uric acid may be a marker of compromised hepatic ATP homeostasis.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; and.
authors.forename: John L
authors.initials: JL
authors.lastname: Petrie
authors.forename: Gillian L
authors.initials: GL
authors.lastname: Patman
authors.forename: Ishita
authors.initials: I
authors.lastname: Sinha
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Alexander
authors.forename: Helen L
authors.initials: HL
authors.lastname: Reeves
authors.forename: Loranne
authors.initials: L
authors.lastname: Agius
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D006305:Health Status Indicators; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008297:Male; D008659:Metabolic Diseases / Q000175:diagnosis / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D014527:Uric Acid / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D014527:Uric Acid; D000255:Adenosine Triphosphate
keywords: fructose; hyperuricemia; mitochondrial function; nonalcoholic fatty liver disease