Effect of Ethanol on Uric Acid Production of Human Liver

Grunst, J.; Dietze, Gabriele; Wicklmayr, M.

doi:10.1159/000176139

Cited by 24 publications

(6 citation statements)

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“…The validity of the rodent model for human liver metabolism is well supported by noninvasive NMR imaging of the temporal changes in liver P i and ATP after fructose challenge (21). In the rat hepatocyte model, the basal rate of UAP was comparable to the rate in human liver (14,15), and it was stimulated more than twofold during inhibition of mitochondrial respiration or during depletion of ATP with fructose or glycerol. However, it was not affected by ethanol or acetate, which did not lower cell ATP.…”

Section: Discussionmentioning

confidence: 96%

“…Acute stimulation of UAP by ethanol was shown by catheterization of the hepatic vein (14). However, whether this was because of a direct effect of ethanol metabolism by hepatocytes or may have resulted from secondary endocrine or autonomic stimuli (25) induced by the ethanol infusion could not be ascertained from the in vivo study (14).…”

Section: Discussionmentioning

confidence: 99%

“…The basal rate of hepatic UAP in humans, determined by catheterization of the hepatic vein, is 3-5 nmol·min Ϫ1 ·g Ϫ1 and is increased severalfold during intravenous fructose infusion (14,15). In rat hepatocytes, the rate of UAP from endogenous substrates determined in basal medium with oxonic acid, to inhibit uric acid degradation by uricase (5), was 6.7 Ϯ 2.5 nmol·h ( Fig.…”

Section: Uap From Endogenous Substrates In Hepatocytesmentioning

confidence: 99%

“…Ethanol consumption is implicated as a cause of hyperuricemia (13,14,24,43), and combined administration of ethanol (0.7 mol) and glycerol (0.02 mol) caused a similar elevation of serum uric acid in humans as fructose (0.4 mol) (38). We tested the separate effects of glycerol and ethanol (Fig.…”

Section: Uap From Endogenous Substrates In Hepatocytesmentioning

confidence: 99%

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

Petrie

Patman

Sinha

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Petrie JL, Patman GL, Sinha I, Alexander TD, Reeves HL, Agius L. The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis. Am J Physiol Endocrinol Metab 305: E1255-E1265, 2013. First published September 17, 2013; doi:10.1152/ajpendo.00214.2013.-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 Ͻ10% of the maximum rate with saturating concentrations of purine substrates. It was marginally (ϳ20%) 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. nonalcoholic fatty liver disease; hyperuricemia; fructose; mitochondrial function PLASMA LEVELS OF URIC ACID, the final product of purine degradation in humans (Fig. 1), are strongly associated with insulin resistance (39) and with nonalcoholic fatty liver disease (NAFLD) (2,20,28). Plasma uric acid reflects the balance between endogenous production by the liver and excretion by the kidney and gut (29). Genome meta-analyses identified common variants in the GCKR gene, which encodes the inhibitor protein of liver glucokinase (GCK) in association with raised serum uric acid levels (18,19,44), and functional studies confirmed a link between GCKR expression in hepatocytes and uric acid production (UAP) (3, 5). However, the minor GCKR variant that associates with raised uric acid levels and hepatic steatosis is associated with decreased rather than increased insulin resistance (26, 31). This indicates that other factors must contribute to the association of hyperuricemia and insulin resistance (39).Lifestyle factors linked to hyperuricemia include obesity and consumption of fructose or ethanol (1, 39, 43). Of these, fr...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Uap From Endogenous Substrates In Hepatocytesmentioning

confidence: 99%

Section: Uap From Endogenous Substrates In Hepatocytesmentioning

confidence: 99%

See 2 more Smart Citations

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

Petrie

Patman

Sinha

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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show abstract

“…Hyperuricosuria is the major risk factor in uric acid lithiasis, and the most common cause of hyperuricosuria is an increased dietary intake of purine 12,13 . Ingestion of uricosuric drugs, 14 ethanol consumption 15 and obesity 16 were shown to be associated with excessive purine production, uricosuria and stone formation. Several acquired and hereditary diseases, and hematological disorders associated with increased bone marrow activity may also lead to hyperuricosuria 17 .…”

Section: Discussionmentioning

confidence: 99%