Uric Acid and Fructose: Potential Biological Mechanisms

doi:10.1016/j.semnephrol.2011.08.006

Seminars in Nephrology

Volume 31, Issue 5, September 2011, Pages 426-432

Presented in part and published in abstract form at the 40th Annual Meeting of the American Society of Nephrology, October 31-November 5, 2007, San Francisco, CA (J Am Soc Nephrol 2007;18:184A [abstract F-PO376]).

https://doi.org/10.1016/j.semnephrol.2011.08.006 Get rights and content

Summary

Excessive fructose consumption is associated with the development of metabolic syndrome and type II diabetes. Both conditions are well-known risk factors for cardiovascular and renal diseases. Uric acid synthesis is linked biochemically to fructose metabolism, thus the widespread consumption of this monosaccharide has been related to steady increasing levels of serum uric acid during the past few decades. Recent evidence has suggested that uric acid may act as a cardiorenal toxin. In this regard, experimental studies have suggested that the primary noxious effect of uric acid occurs inside the cell and is likely the stimulation of oxidative stress. More studies to disclose the harmful mechanisms associated with increasing intracellular uric acid levels after a fructose load are warranted.

Section snippets

Fructose Metabolism

The metabolism of fructose is different in many ways from that of glucose. First, the rate of the body's use of fructose is fast and exceeds that of glucose; second, the uptake of fructose lacks a negative feedback mechanism, which explains its excessive catabolism when high doses are consumed.³ The liver is the primary site of dietary fructose metabolism after intestinal absorption in the jejunum. Fructose uptake is mediated by the fructose-specific transporter GLUT5 and glucose-fructose

Classic Deleterious Mechanisms Associated with Fructose Consumption

Several mechanisms have been proposed by which high loads of fructose have damaging effects. For example, dyslipidemia secondary to fructose consumption is associated with increased risk for developing cardiovascular disease, insulin resistance, abdominal obesity, and type 2 diabetes.¹²

Oxidative stress is another effect secondary to fructose ingestion; thus, this monosaccharide has been shown to be more reactive than glucose in its ability to form advanced glycation end products (AGEs).¹⁵

Renal Effects of Fructose

There is a substantial amount of information related to the effects of fructose on renal tissue. Fructose exerts its damaging effects on kidneys as a consequence of the high load that reaches this organ, as is suggested by the increased urinary excretion of this sugar when exposed to high doses.²² In addition, the kidney strongly expresses GLUT5 and KHK-C, mainly in the renal proximal tubule.⁵ Moreover, fructose exposure up-regulates the expression of both proteins in renal tissue, indicating

Hyperuricemia: A Novel Injurious Mechanism Induced by Fructose Ingestion

Some epidemiologic studies have found that increased levels of plasma UA correlate with the consumption of sugary beverages,27, 28, 29, 30, 31 which indirectly imply increased fructose consumption because these items are sweetened mainly with HFCS, which contains 55% fructose, or sucrose, which contains 50% fructose. Because of the intermittent nature of UA synthesis induced by fructose, the increments of serum UA should be better observed in postprandial conditions and mainly after a rich

Conclusions

In conclusion, the ingestion of excessive fructose from added sugars such as sucrose or HFCS can induce features of metabolic syndrome, fatty liver, and renal injury. The unique ability of fructose to induce these changes appears to be specific to its metabolism, which results in transient ATP depletion and intracellular UA generation. Increasing evidence suggests that the increase in intracellular UA may result in the induction of oxidative stress, perhaps by stimulating NADPH oxidase. In

Acknowledgment

The authors thank Dr. Richard J. Johnson for his valuable suggestions.

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Targeted and non-targeted metabolomics uncovering the effects of Er-Miao-Wan formula on rats with hyperuricemia
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Er-Miao-Wan formula (EMW), composed of Phellodendri Chinensis Cortex and Atractylodis Rhizoma, is widely used in the treatment of hyperuricemia (HUA), gout, and related complications as a classic compound formula. However, its mechanisms for the treatment of HUA still need to be further systematically investigated. The study aimed to perform modern analytical techniques to elucidate the mechanisms of EMW in improving the symptoms of HUA from the perspective of metabolomics. We used a high-fructose diet to establish a rat model of HUA to evaluate the effects of EMW on improving HUA. Next, we established a targeted metabolomics analysis method to quantitatively analyze purine metabolites in plasma by using ultra-high-performance liquid chromatography with ultraviolet and triple quadrupole mass spectrometry (UHPLC-UV-QQQ MS), and combined with plasma non-targeted metabolomics analysis by using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q/TOF MS) to clarify the potential mechanisms of EMW to improve HUA. Oral administration of EMW could significantly increase the urinary uric acid and decrease the serum uric acid, and exhibited a remarkable effect on improving HUA. Plasma targeted metabolomics analysis showed that six purine metabolites related to HUA, including uric acid, hypoxanthine, xanthine, deoxyadenosine, deoxyguanosine, and deoxyinosine, were changed in the EMW-treated group. Further, principal component analysis (PCA) and partial least squares discrimination analysis (PLS-DA) showed that the mechanism of EMW interfering with purine metabolic pathway in the rats with HUA could be different from that of allopurinol. On the basis of plasma non-targeted metabolomics, PCA and orthogonal partial least squares discriminant analysis (OPLA-DA) screened and identified 23 potential biomarkers in the rats with HUA, and 11 biomarkers showed a trend of reversion after the intervention of EMW. The pathway analysis suggested that EMW might have therapeutic effects on the rats with HUA via the metabolic pathways including phenylalanine metabolism, glycerophospholipid metabolism, and tryptophan metabolism. In this study, a plasma targeted metabolomics method that can simultaneously quantify nine purine metabolites in rats with HUA was established for the first time, which can be used to study diseases closely related to HUA. In addition, we further explored the overall effect of EMW on HUA in combination with the metabonomic method established by non-targeted metabolomics, which was helpful to solve the defect that the pharmacological mechanism caused by multi-components and multi-targets of traditional Chinese medicine was difficult to explain scientifically and comprehensively. In summary, EMW could effectively alleviate the symptoms of high-fructose-induced HUA, and the study provided a reference for the potential therapeutic mechanism of EMW.
Untargeted metabolomics reveal the therapeutic effects of Ermiao wan categorized formulas on rats with hyperuricemia
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Citation Excerpt :
Under the action of fructokinase, fructose was rapidly phosphorylated and enters the lipid metabolism pathway, contributing to steatosis and to increased circulating triglyceride levels in the form of very low-density lipoprotein (VLDL) (Sobrecases et al., 2010). Decreases in intracellular free phosphate due to rapid hepatic fructose phosphorylation could increase uric acid production through activation of AMP deaminase, which leads to catabolism of AMP to uric acid (Lanaspa et al., 2011). Therefore, hyperuricemia could directly affect the homeostasis of energy metabolism in the body.
Ermiao wan (2 MW) is one of the most frequently prescription in traditional Chinese medicine (TCM) to treat hyperuricemia. Sanmiao wan (3 MW) and Simiao wan (4 MW), two modified Ermiao wan, also show good clinical effects in the treatment of gout and hyperuricemia. However, their uric acid lowering effects and potential action mechanism still need to be systematically investigated.
The aim of present study was to analyze and compare the uric acid-lowering effects of 2 MW, 3 MW and 4 MW in rat with high fructose combined with potassium oxonate (HFCPO)-induced hyperuricemia and their possible mechanisms through plasma metabolomics methods.
HFCPO-induced hyperuricemia rat model was established to evaluate the therapeutic effects of Ermiao wan categorized formulas (ECFs, including 2 MW, 3 MW and 4 MW). Body weight, blood uric acid, creatinine, urine uric acid and urine creatinine levels and histopathological parameters of rats were assessed. Plasma untargeted metabolomics based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) was established to collect the metabolic profiles of rats and explore the metabolic changes that occurred after each ECFs treatment.
Oral administration of ECFs could decrease the level of blood uric acid, creatinine and increase the level of urine uric acid and urine creatinine in varying degrees, and alleviated hepatocyte steatosis and atrophy and degeneration of glomerulus, vacuolar degeneration of renal tubular epithelial cells in HFCPO-induced hyperuricemia rats. Plasma untargeted metabolomics analysis showed that significant alterations were observed in metabolic signatures between the HFCPO-induced hyperuricemia group and control group. Thirty five potential biomarkers in rat plasma were identified in the screening by principal component analysis (PCA), partial least squares discrimination analysis (PLS-DA) and orthogonal partial least squares discrimination analysis (OPLS-DA). Differential metabolites related to hyperuricemia, including acylcarnitines and amino acid related metabolites, were further used to indicate relevant pathways in hyperuricemia rats, including tryptophan metabolism, arginine biosynthesis, purine metabolism, arginine and proline metabolism, beta-alanine metabolism, citrate cycle (TCA cycle), glycerophospholipid metabolism and linoleic acid metabolism. 2 MW, 3 MW and 4 MW could invert the pathological process of hyperuricemia to varying degrees through in part regulating the perturbed lipid metabolic pathway. 4 MW were better than 2 MW and 3 MW in the intervention of the disordered tricarboxylic acid metabolism and purine metabolism caused by hyperuricemia.
In summary, ECFs treatment could effectively alleviate symptoms of hyperuricemia and regulate metabolic disorders in HFCPO-induced hyperuricemia rats.
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Mice were fed a normal diet, a high-fructose diet, or high-fructose diet with DM9218. Metabolic parameters, fructose- and UA-related metabolites, and fecal microbiota were investigated. Whole-genome sequencing of strain DM9218 was also conducted. In addition, an inosine hydrolase from DM9218 was heterologously expressed in Escherichia coli, and its inosine-degrading activity was detected.
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Uric Acid and Fructose: Potential Biological Mechanisms

Summary

Section snippets

Fructose Metabolism

Classic Deleterious Mechanisms Associated with Fructose Consumption

Renal Effects of Fructose

Hyperuricemia: A Novel Injurious Mechanism Induced by Fructose Ingestion

Conclusions

Acknowledgment

J Pediatr

Blood

Metabolism

Kidney Int

Kidney Int

Kidney Int

J Pediatr

Am J Hypertens

Int J Cardiol

Kidney Int

Metabolic effects of fructose and the worldwide increase in obesity

Physiol Rev

Increased fructose associates with elevated blood pressure

J Am Soc Nephrol

Metabolic effects of dietary fructose

FASEB J

Sugar sensing by enterocytes combines polarity, membrane bound detectors and sugar metabolism

J Cell Physiol

Dietary fructose causes tubulointerstitial injury in the normal rat kidney

Am J Physiol Renal Physiol

Ketohexokinase: expression and localization of the principal fructose-metabolizing enzyme

J Histochem Cytochem

Properties of normal and mutant recombinant human ketohexokinases and implications for the pathogenesis of essential fructosuria

Diabetes

GLUT2 mutations, translocation, and receptor function in diet sugar managing

Am J Physiol Endocrinol Metab

Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes?

Endocr Rev

Fructose metabolism in the human erythrocytePhosphorylation to fructose 3-phosphate

Biochem J

The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome

Nat Rev Gastroenterol Hepatol

Fructose: a highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic syndrome

Am J Physiol Endocrinol Metab

Hereditary fructose intolerance

J Med Genet