Uric Acid Synthesis Research Articles

Phyllanthi Fructus ameliorates hyperuricemia and kidney injure via inhibiting uric acid synthesis, modulating urate transporters, and alleviating inflammation

Phyllanthi Fructus ameliorates hyperuricemia and kidney injure via inhibiting uric acid synthesis, modulating urate transporters, and alleviating inflammation

Host-derived Lactobacillus plantarum alleviates hyperuricemia by improving gut microbial community and hydrolase-mediated degradation of purine nucleosides.

The gut microbiota is implicated in the pathogenesis of hyperuricemia (HUA) and gout. However, it remains unclear whether probiotics residing in the host gut, such as Lactobacillus, can prevent HUA development. Herein, we isolated Lactobacillus plantarum SQ001 from the cecum of HUA geese and conducted in vitro assays on uric acid (UA) and nucleoside co-culture. Metabolomics and genome-wide analyses, revealed that this strain may promote nucleoside uptake and hydrolysis through its nucleoside hydrolase gene. The functional role of iunH gene was confirmed via heterologous expression and gene knockout studies. Oral administration of L. plantarum SQ001 resulted in increased abundance of Lactobacillus species and reduced serum UA levels. Furthermore, it downregulated hepatic xanthine oxidase, a key enzyme involved in UA synthesis, as well as renal reabsorption protein GLUT9, while enhancing the expression of renal excretion protein ABCG2. Our findings suggest that L. plantarum has potential to ameliorate gut microbial dysbiosis with HUA, thereby offering insights into its potential application as a probiotic therapy for individuals with HUA or gout.

Xanthine oxidoreductase: structure, distribution and physioloical role

The article presents an overview of the modern literature on the structure, distribution, biological and physiological role of xanthine oxidoreductase (XOR). XOR has been identified in all living organisms, from bacteria to humans. However, only in mammals it is presented in two forms, other species contain exclusively the XDH form. The enzyme is a homodimer with independent electron transfer in each monomer. XOR catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid in the final stage of purine metabolism and is widely distributed enzyme. The review highlights the forms of XOR and their role in the generation of reactive oxygen species (ROS), reactive nitrogen species (RNS) and synthesis of uric acid which are involved in many physiological processes. Uric acid shows antioxidant activity, and ROS and RNS play a role in innate immunity, in signaling, metabolism of xenobiotics, regulation of cellular redox potential and are also involved in mammogenesis and lactogenesis. Thus, in recent years significant progress has been made in understanding the biochemical and physiological nature of this enzyme system.

Polysaccharides from Alpinia oxyphylla fruit prevent hyperuricemia by inhibiting uric acid synthesis, modulating intestinal flora and reducing renal inflammation

Hyperuricemia (HUA) is one of the most common chronic diseases today, with a prevalence exceeding 14 % in both the United States and China. Current clinical treatments for HUA focus on promoting uric acid (UA) excretion and inhibiting UA production, but often neglect the strain on the liver and kidneys. The fruit of Alpinia oxyphylla (A. oxyphylla) is known to improve renal function, regulate metabolism, and exhibit anti-inflammatory effects; however, its effectiveness and mechanisms in treating HUA are not well understood. In this study, HUA mice induced by potassium oxonate and adenine were treated with A. oxyphylla polysaccharide (AFP) for 21 days. The levels associated with HUA were quantified using assay kits to evaluate the impact of AFP on HUA. Serum metabolomics and 16S rRNA sequencing were used to investigate the mechanisms by which AFP ameliorates HUA. The results showed that AFP treatment reduced abnormal biochemical levels, including UA, blood urea nitrogen, and creatinine, in HUA mice. AFP inhibited UA synthesis by regulating pyrimidine metabolism and the metabolism of alanine, aspartate and glutamate, reduced kidney inflammation, and promoted UA excretion by regulating intestinal flora. Thus, AFP appears to be an effective agent for alleviating HUA symptoms.

Targeting Liver Xor by GalNAc-siRNA Is an Effective Strategy for Hyperuricemia Therapy.

Hyperuricemia, i.e., increased plasma uric acid concentration, is a common problem in clinical practice, leading to gout or nephrolithiasis, and is associated with other disorders, such as metabolic syndrome, cardiovascular disease, and chronic renal disease. Xanthine oxidoreductase (XOR) is a critical rate-limiting enzyme involved in uric acid synthesis and a promising target for hyperuricemia therapy. However, XOR inhibitors currently face clinical problems such as a short half-life and side effects. Here, we found that specifically targeting liver Xor with GalNAc-siRNAs had a good therapeutic effect on hyperuricemia. First, siRNAs were designed to target various sites in the homologous region between Homo sapiens and Mus musculus Xor mRNA and were screened in primary mouse hepatocytes. Then, the siRNAs were modified to increase their stability in vivo and conjugated with GalNAc for liver-specific delivery. The effects of GalNAc-siRNAs were evaluated in three hyperuricemia mouse models, including potassium oxonate and hypoxanthine administration in WT and humanized XDH mice and Uox knockout mice. Febuxostat, a specific XOR inhibitor used for hyperuricemia treatment, was used as a positive control. Targeting liver Xor with GalNAc-siRNAs by subcutaneous administration reduced plasma uric acid levels, uric acid accumulation in the kidney, renal inflammation, and fibrosis, thereby alleviating kidney damage in hyperuricemia mouse models without hepatoxicity. The results demonstrated that targeting liver Xor with GalNAc-siRNAs was a promising strategy for hyperuricemia therapy.

Research progress on the effects of sodium-glucose linked transporter 2 inhibitors on multiple metabolic disorders in metabolic syndrome.

Metabolic syndrome is a complex group of metabolic disorders with an increasing global incidence rate, posing a serious threat to human health. Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a new type of oral hypoglycemic drug. SGLT2 inhibitors not only lower blood glucose level in a non-insulin-dependent manner by inhibiting glucose reabsorption by renal proximal convoluted tubular epithelial cell to promote urinary glucose excretion, but also by improving islet β cell function, reducing inflammatory responses, and inhibiting oxidative stress. In addition, SGLT2 inhibitors can reduce body weight through osmotic diuresis and increase fat metabolism; reduce blood pressure by inhibiting excessive activation of sympathetic nervous system and by improving vascular function. They can also improve blood lipids by increasing degradation of triacylglycerol; reduce blood uric acid by promoting uric acid excretion in kidney and intestine, and by reducing uric acid synthesis. This article reviews the effects and mechanisms of SGLT2 inhibitors on multiple metabolic disorders in metabolic syndrome and explores their potential application in metabolic syndrome treatment.

Mechanism of flavonoids in the treatment of gouty arthritis (Review).

The present review expounds the advancements in the application and mechanisms of flavonoids in gouty arthritis, highlighting their significance in managing the disease. Gouty arthritis is among the most common and severe inflammatory diseases, caused by hyperuricemia and the deposition of sodium urate crystals in the joints and surrounding tissues, posing a serious threat to human life and health. Flavonoids, extracted from various herbs, have attracted significant attention due to their efficacy in improving gouty arthritis. The present study systematically reviews the in vivo studies and in vitro animal studies on flavonoids from herbal medicines for the treatment of gouty arthritis that have been previously published in the PubMed, ScienceDirect, Google Scholar and China National Knowledge Infrastructure databases between 2000 and 2023. The review of the literature indicated that flavonoids can improve gouty arthritis through multiple mechanisms. These include lowering xanthine oxidase activity, inhibiting uric acid (UA) synthesis, regulating UA transporters to promote UA excretion, reducing the inflammatory response and improving oxidative stress. These mechanisms predominantly involve regulating the NOD‑like receptor 3 inflammasome, the Toll‑like receptor 4/myeloid differentiation factor 88/nuclear factor‑κB signaling pathway, and the levels of UA transporter proteins, namely recombinant urate transporter 1, glucose transporter 9, organic anion transporter (OAT)1 and OAT3. Various flavonoids used in traditional Chinese medicine hold therapeutic promise for gouty arthritis and are anticipated to pave the way for novel pharmaceuticals and clinical applications.

Knowledge, Attitudes, and Practices about Hyperuricemia and Gout in Community Health Workers and Patients with Diabetes.

Hyperuricemia exhibits a high incidence among individuals with diabetes; however, the significance of hyperuricemia and gout is often underestimated. This study aimed to assess the knowledge, attitude, and practice of hyperuricemia and gout among community health workers and patients with diabetes. Two questionnaires were designed to investigate knowledge, attitudes, and practices of hyperuricemia and gout among community health workers and patients with diabetes in Chenghua District, Chengdu, from August 2021 to January 2022. A total of 709 community health workers were included, whose average score was 17.74/30. Approximately half of general practitioners (GPs) demonstrated knowledge regarding the target serum uric acid levels for hyperuricemia and gout. Only 11.2% of GPs were fully aware of the preferred medicine for acute gout. The majority of GPs (86.7%) demonstrated limited awareness regarding the contraindications associated with colchicine, while a significant proportion (65.1%) lacked knowledge about the specific classes of drugs that inhibit uric acid synthesis. Among the 508 patients with diabetes included in this survey, 32.3% demonstrated awareness of hyperuricemia, while 60.8% exhibited knowledge regarding gout. The average score attained by these individuals was recorded at 7.21 out of a total of 26 points. The majority of patients with diabetes (87.8%) held the mistaken belief that hyperuricemia definitely led to the development of gout. Almost 66% agreed that a massage or a hot compress could be used when acute gouty arthritis attacks. The knowledge rate of hyperuricemia and gout among community health workers was moderate, while it was low in patients with diabetes.

Uric acid-lowering effect of harpagoside and its protective effect against hyperuricemia-induced renal injury in mice

Hyperuricemia (HUA) is caused by increased synthesis and/or insufficient excretion of uric acid (UA). Long-lasting HUA may lead to a number of diseases including gout and kidney injury. Harpagoside (Harp) is a bioactive compound with potent anti-inflammatory activity from the roots of Scrophularia ningpoensis. Nevertheless, its potential effect on HUA was not reported. The anti-HUA and nephroprotective effects of Harp on HUA mice were assessed by biochemical and histological analysis. The proteins responsible for UA production and transportation were investigated to figure out its anti-HUA mechanism, while proteins related to NF-κB/NLRP3 pathway were evaluated to reveal its nephroprotective mechanism. The safety was evaluated by testing its effect on body weight and organ coefficients. The results showed that Harp significantly reduced the SUA level and protected the kidney against HUA-induced injury but had no negative effect on safety. Mechanistically, Harp significantly reduced UA production by acting as inhibitors of xanthine oxidase (XOD) and adenosine deaminase (ADA) and decreased UA excretion by acting as activators of ABCG2, OAT1 and inhibitors of GLUT9 and URAT1. Moreover, Harp markedly reduced infiltration of inflammatory cells and down-regulated expressions of TNF-α, NF-κB, NLRP3 and IL-1β in the kidney. Harp was a promising anti-HUA agent.

Quercetin ameliorates hyperuricemic nephropathy by repressing uric acid synthesis and reabsorption in mice and cells

AbstractHyperuricemia as one of the key factors for gout, and quercetin could reduce the uric acid (UA) content. However, the mechanism of quercetin reduces UA content is still uncovered. Herein, we found quercetin can reduce UA content, induce antioxidant enzyme activity, inhibit the enzyme activity of xanthine oxidase (XOD) in hyperuricemia mice. Moreover, the UA reabsorption was also significantly reduced in the kidney and the kidney inflammation was alleviated by quercetin in hyperuricemia mice. Meanwhile, the protein level of ATP‐binding cassette super‐family G member 2 (ABCG2) was markedly induced and the protein levels of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) were significantly repressed by quercetin in hyperuricemia mice and HK‐2 cells and by quercetin‐3‐O‐glucuronide in HK‐2 cells. Additionally, the docking mode indicated that quercetin is stable bound to the active site of XOD. Overall, the data reveal that quercetin alleviates hyperuricemia by repressing the activity of XOD, reducing the UA absorption via enhancing ABCG2 expression, and repressing URAT1 and GLUT9 expression.

Hesperitin-Copper(II) Complex Regulates the NLRP3 Pathway and Attenuates Hyperuricemia and Renal Inflammation.

Hyperuricaemia (HUA) is a disorder of purine metabolism in the body. We previously synthesized a hesperitin (Hsp)-Cu(II) complex and found that the complex possessed strong uric acid (UA)-reducing activity in vitro. In this study we further explored the complex's UA-lowering and nephroprotective effects in vivo. A mouse with HUA was used to investigate the complex's hypouricemic and nephroprotective effects via biochemical analysis, RT-PCR, and Western blot. Hsp-Cu(II) complex markedly decreased the serum UA level and restored kidney tissue damage to normal in HUA mice. Meanwhile, the complex inhibited liver adenosine deaminase (ADA) and xanthine oxidase (XO) activities to reduce UA synthesis and modulated the protein expression of urate transporters to promote UA excretion. Hsp-Cu(II) treatment significantly suppressed oxidative stress and inflammatory in the kidney, reduced the contents of cytokines and inhibited the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) inflammatory pathway. Hsp-Cu(II) complex reduced serum UA and protected kidneys from renal inflammatory damage and oxidative stress by modulating the NLRP3 pathway. Hsp-Cu(II) complex may be a promising dietary supplement or nutraceutical for the therapy of hyperuricemia.

A System for Discovering Novel Uricosurics Targeting Urate Transporter 1 Based on In Vitro and In Vivo Modeling.

Hyperuricemia has become a global burden with the increasing prevalence and risk of associated metabolic disorders and cardiovascular diseases. Uricosurics act as a vital urate-lowering therapy by promoting uric acid excretion via the kidneys. However, potent and safe uricosurics are still in urgent demand for use in the clinic. In this study, we aimed to establish in vitro and in vivo models to aid the discovery of novel uricosurics, and to search for potent active compounds, especially targeting urate transporter 1 (URAT1), the major urate transporter in the kidney handling uric acid homeostasis. As a result, for preliminary screening, the in vitro URAT1 transport activity was assessed using a non-isotopic uric acid uptake assay in hURAT1-stably expressed HEK293 cells. The in vivo therapeutic effect was evaluated in a subacute hyperuricemic mouse model (sub-HUA) and further confirmed in a chronic hyperuricemic mouse model (Ch-HUA). By utilizing these models, compound CC18002 was obtained as a potent URAT1 inhibitor, with an IC50 value of 1.69 μM, and favorable uric acid-lowering effect in both sub-HUA and Ch-HUA mice, which was comparable to that of benzbromarone at the same dosage. Moreover, the activity of xanthine oxidoreductase, the key enzyme catalyzing uric acid synthesis, was not altered by CC18002 treatment. Taken together, we have developed a novel screening system, including a cell model targeting URAT1 and two kinds of mouse models, for the discovery of novel uricosurics. Utilizing this system, compound CC18002 was investigated as a candidate URAT1 inhibitor to treat hyperuricemia.

Whey Protein Peptide Pro-Glu-Trp Ameliorates Hyperuricemia by Enhancing Intestinal Uric Acid Excretion, Modulating the Gut Microbiota, and Protecting the Intestinal Barrier in Rats.

Hyperuricemia (HUA) is a metabolic disorder characterized by an increase in the concentrations of uric acid (UA) in the bloodstream, intricately linked to the onset and progression of numerous chronic diseases. The tripeptide Pro-Glu-Trp (PEW) was identified as a xanthine oxidase (XOD) inhibitory peptide derived from whey protein, which was previously shown to mitigate HUA by suppressing UA synthesis and enhancing renal UA excretion. However, the effects of PEW on the intestinal UA excretion pathway remain unclear. This study investigated the impact of PEW on alleviating HUA in rats from the perspective of intestinal UA transport, gut microbiota, and intestinal barrier. The results indicated that PEW inhibited the XOD activity in the serum, jejunum, and ileum, ameliorated intestinal morphology changes and oxidative stress, and upregulated the expression of ABCG2 and GLUT9 in the small intestine. PEW reversed gut microbiota dysbiosis by decreasing the abundance of harmful bacteria (e.g., Bacteroides, Alloprevotella, and Desulfovibrio) and increasing the abundance of beneficial microbes (e.g., Muribaculaceae, Lactobacillus, and Ruminococcus) and elevated the concentration of short-chain fatty acids. PEW upregulated the expression of occludin and ZO-1 and decreased serum IL-1β, IL-6, and TNF-α levels. Our findings suggested that PEW supplementation ameliorated HUA by enhancing intestinal UA excretion, modulating the gut microbiota, and restoring the intestinal barrier function.

A metabolomics perspective reveals the mechanism of the uric acid-lowering effect of Prunus salicina Lindl. cv. "furong" polyphenols in hypoxanthine and potassium oxybate-induced hyperuricemic mice.

The incidence of hyperuricemia (HUA) shows a gradually increasing trend towards affecting younger individuals, and it can significantly harm the overall health status of the body. Based on a metabolomics perspective, this study reveals the mechanism of the uric acid-lowering action of Prunus salicina Lindl. cv. "furong" polyphenols (PSLP) on a hyperuricemia mouse model induced by hypoxanthine and potassium oxybutyrate. The results demonstrate that PSLP comprise an effective treatment strategy for reducing the levels of serum uric acid (SUA), serum creatinine (SCr) and blood urea nitrogen (BUN) in HUA mice (p < 0.05), wherein the maximum decrease rates are up to 44.50%, 29.46%, and 32.95%, respectively. PSLP are observed to exert a pronounced inhibitory effect on the activities of xanthine oxidase (XOD) and adenosine deaminase (ADA) in the livers of HUA mice, with reductions of up to 16.36% and 20.13%, respectively. These findings illustrate that PSLP exert a significant uric acid-lowering effect. Subsequent metabolomic analysis of mouse serum identified 28 potential biomarkers for hyperuricemia, whose levels were markedly diminished by PSLP. This process involved alterations in purine, glycine, the pentose phosphate pathway, and galactose metabolism. Twenty-eight potential biomarkers were identified for hyperuricemia by subsequent metabolomic analysis of mouse serum, whose levels were markedly reversed by PSLP intervention. The regulation of HUA by PSLP involved alterations in purine metabolism, glycerolipid metabolism, the pentose phosphate pathway, and galactose metabolism. The mechanism of PSLP ameliorated hyperuricemia might be attributed to reduction of the level of the uric acid precursor ribose-5-phosphate in the pentose phosphate pathway, the inhibition of the activities of uric acid synthase XOD and ADA in purine metabolism, and reduction of the synthesis of the end product uric acid. This study provides a theoretical basis for the development of functional foods based on PSLP, which can potentially reduce uric acid levels.

Lactococcus cremoris D2022 alleviates hyperuricemia and suppresses renal inflammation via potential gut-kidney axis.

Hyperuricemia (HUA) is a widespread metabolic disorder. Probiotics have drawn increasing attention as an adjunctive treatment with fewer side effects. However, thus far the effective strains are limited and the mechanisms for their serum uric acid (SUA)-lowering effect are not well understood. Along this line, we conducted the current study using a hyperuricemia mouse model induced by potassium oxonate and adenine. A novel strain of Lactococcus cremoris named D2022 was identified to have significant SUA-lowering capability. Lactococcus cremoris D2022 significantly reduced SUA levels by inhibiting uric acid synthesis and regulating uric acid transportation. It was also found that Lactococcus cremoris D2022 alleviated HUA-induced renal inflammatory injury involving multiple signaling pathways. By focusing on the expression of NLRP3-related inflammatory genes, we found correlations between the expression levels of these genes and free fatty acid receptors (FFARs). In addition, oral administration of Lactococcus cremoris D2022 increased short-chain fatty acids (SCFAs) in cecal samples, which may be one of the mechanisms by which oral probiotics alleviate renal inflammation. Serum untargeted metabolomics showed changes in a variety of serum metabolites associated with purine metabolism and inflammation after oral administration of Lactococcus cremoris D2022, further confirming its systemic bioactivity. Finally, it was proved that Lactococcus cremoris D2022 improved intestinal barrier function. In conclusion, Lactococcus cremoris D2022 can alleviate HUA and HUA-induced nephropathy by increasing the production of SCFAs in the gut and systemic metabolism.

Commensal Enterococcus faecalis W5 ameliorates hyperuricemia and maintains the epithelial barrier in a hyperuricemia mouse model.

The intestine is responsible for approximately one-third of uric acid (UA) excretion. The effect of commensal Enterococcus faecalis (E. faecalis), one of the most colonized bacteria in the gut, on UA excretion in the intestine remains to be investigated. The aim of this study was to evaluate the effect of commensal E. faecalis on UA metabolism and gut microbiota. The 16SrRNA gene sequencing was used to examine the species of Enterococcus in mouse fecal content. E. faecalis strain was isolated from mouse feces and identified to be E. faecalis W5. The hyperuricemia (HUA) animal model was established with yeast-rich forage and 250 mg·kg-1 ·day-1 potassium oxonate. Oral administration of E. faecalis W5 was given for 20 days, serving as the Efa group. Disrupted intestinal barrier, activated proinflammatory response and low UA excretion in the intestine were found in HUA mice. After E. faecalis W5 treatment, the gut barrier was restored and serum UA level was decreased. Additionally, fecal and intestinal UA levels were elevated, intestinal urate transporter ABCG2 and purine metabolism were upregulated. Moreover, short-chain fatty acid levels were increased, and intestinal inflammation was ameliorated. Commensal E. faecalis W5 ameliorated HUA through reversing the impaired gut barrier, promoting intestinal UA secretion by regulating ABCG2 expression, and decreasing intestinal UA synthesis by regulating purine metabolism. The results may provide the potential for developing treatments for HUA through the intestine.

Amelioration of hyperuricemia by Lactobacillus acidophilus F02 with uric acid-lowering ability via modulation of NLRP3 inflammasome and gut microbiota homeostasis

Hyperuricemia is a metabolic disease caused by disturbances in purine metabolism and imbalances in the formation and excretion of uric acid. It is closely related to the gut microbiota, which is considered a therapeutic target. Some lactic acid bacteria with a uric acid lowering effect have the potential to ameliorate hyperuricemia in the host. However, the mechanism of action remains unclear. Here, we screened a strain of Lactobacillus acidophilus F02 that efficiently degrades uric acid precursors (inosine and guanosine) and further investigated its underlying mechanism on the alleviation of hyperuricemia in high fructose-adenine induced mice. Results showed that L. acidophilus F02 administration reduced serum uric acid levels in hyperuricemia mice by inhibiting xanthine oxidase and adenosine deaminase activity, while protecting hepatorenal injury and systemic inflammation by regulating the relative expression of NLRP3 inflammasome. Most importantly, it restored gut microbial homeostasis and the abundance of bacterial taxa (i.e., a balance in the relative abundance of Firmicutes and Actinobacteria and an increase in the abundance of Bacteroides, Ruminococcus and Lactobacillus). Furthermore, the ability of L. acidophilus F02 to lower uric acid and suppress NLRP3 inflammasome expression was confirmed in the HK-2 cell model, as well as the multiple immunomodulatory effects on RAW264.7 cells. Taken together, we speculate that fructose-adenine induced hyperuricemia triggers hepatorenal injury and gut microbiota dysbiosis, which is ameliorated by L. acidophilus F02. Collectively, the results suggest that lowering uric acid synthesis, increasing uric acid excretion and reducing NLRP3-related IL-1β levels are effective strategies to ameliorate hyperuricemia. Such information could inform future studies on the ecology of L. acidophilus and guide the use of this species for dietary applications in the food industry.

Inhibiting Hepatocyte Uric Acid Synthesis and Reabsorption Ameliorates Acetaminophen-Induced Acute Liver Injury in Mice

Acetaminophen (APAP) overdose is the most common cause of drug-induced liver injury worldwide. Uric acid (UA) is involved in sterile inflammation in many organs, but its role in APAP-induced liver injury remains elusive. We quantified the concentration of UA in the serum and liver tissues of APAP-overdosed mice and explored the changes in proteins involved in UA synthesis, absorption, and degeneration on APAP stimulation. We also examined the effects of inhibiting hepatocyte UA synthesis or reabsorption on APAP-induced liver injury in mice. Furthermore, we explored the process of UA clearance by peripheral macrophages. APAP overdose significantly increased intrahepatic UA contents, which occurred earlier than apparent hepatocyte injury in APAP-overdosed mice. APAP overdose induced significant DNA leakage and may thereby increase the substrate of UA synthesis. APAP overdose also significantly increased the enzymatic activity of xanthine oxidase and urate oxidase and decreased the expression of the UA reabsorption transporter GLUT9 in hepatocytes. Inhibiting hepatocyte UA synthesis by febuxostat or reabsorption by hepatic-specific knockout of GLUT9 alleviated APAP-induced liver injury. Further experiments showed that monosodium urate but not soluble UA may be a major form of UA mediating hepatocyte injury. Additionally, monosodium urate further recruited circulating macrophages into the liver and then aggravated inflammation by increasing the levels of inflammatory factors and reactive oxygen species. Deletion of macrophages significantly ameliorated APAP-induced liver injury in mice. APAP overdose induces excessive UA production and leads to local high concentrations in the liver, which further injures cells and induces liver inflammation. Inhibiting the production of UA may be a potential therapeutic option for treating APAP-induced liver injury.

THU268 Hyperuricemia In Insulin Resistance Is Associated With Increased Synthesis And Not Decreased Renal Excretion Of Uric Acid In Humans

Abstract Disclosure: R. Haykal: None. A. Kinzer: None. B. Abel: None. M. Lightbourne: None. M.S. Startzell: None. E. Cochran: None. R.J. Brown: None. Title: Hyperuricemia in insulin resistance is associated with increased synthesis and not decreased renal excretion of uric acid in humans. Background: In obesity and lipodystrophy (LD), insulin resistance (IR) is “selective”, with lack of insulin signaling causing hyperglycemia, but enhanced insulin signaling causing dyslipidemia. Rare human conditions exist in which there is extreme, non-selective IR impairing all insulin signaling pathways (e.g. mutations of the insulin receptor, INSR), resulting in hyperglycemia without dyslipidemia. We previously found that patients with non-selective IR do not have the hyperuricemia observed in selective IR. Potential mechanisms of hyperuricemia in selective IR include altered expression of renal uric acid transporters leading to impaired uric acid excretion, and increased activity of xanthine oxidoreductase (XOR), causing increased uric acid synthesis. We thus hypothesized that enhanced insulin signaling in selective IR would result in decreased fractional excretion of uric acid (FEUA) and/or increased biomarkers of XOR activity compared to non-selective IR. Method: We conducted 2 cross-sectional analyses of patients with severe IR that was either selective (due to LD) or non-selective (due to INSR mutation). Analysis 1 compared fasting insulin, fasting serum uric acid, and FEUA from 24-hr urine collection in 46 patients with LD and 13 with INSR. Analysis 2 compared products of purine nucleotide catabolism and salvage pathways by untargeted metabolomics in serum of 30 subjects each with LD and INSR. Results: In analysis 1, fasting insulin was lower in LD vs INSR (median 37.5 [25th-75th percentile 23.1-87.0] vs 88.7 [41.9-458.6] mcU/mL; P=0.0097). Serum uric acid was higher in LD vs INSR (5.3±1.6 vs 3.3±1.0 mg/dL; P=0.04). FEUA was comparable in the 2 groups (9.0±5 vs 8.5±3.5%; P=0.75). In analysis 2, uric acid was 1.6 fold higher (P&amp;lt;0.0001) in LD vs INSR. Xanthine, hypoxanthine, and xanthine to hypoxanthine ratio were comparable in both groups, but uric acid to xanthine ratio was 1.5 fold higher (P=0.01) and AMP was 0.8 fold lower in LD vs INSR (P=0.0029). Conclusion: Patients with selective IR due to LD had elevated serum uric acid, consistent with the hyperuricemia seen in selective IR due to obesity. By contrast, patients with non-selective IR due to INSR had lower serum uric acid despite higher fasting insulin. However, FEUA did not differ in these groups, thus hyperuricemia in non-selective IR might not be related to decreased renal excretion of uric acid. Elevated uric acid to xanthine ratio and lower AMP in selective IR suggest increased irreversible conversion of xanthine to uric acid by XOR, precluding salvage of purine nucleotides to AMP. Direct measurement of XOR activity in selective vs non-selective IR is needed to this potential mechanism by which insulin may lead to hyperuricemia. Presentation: Thursday, June 15, 2023

Modification of Pt-Porous Composite Material (Pt-PCM) and Its Application for Electroanalysis of Uric Acid and Electrosynthesis of Acetic Acid from Ethanol

Research on the synthesis of Pt-Porous Composite Material (Pt-PCM) has been done. This material is used for the electrochemical activity of uric acid and electrochemical synthesis of acetic acid from ethanol. Pt-PCM is made by mixing 99.995% platinum powder and PVC or Poly (vinyl chloride) homogeneously with a homogenizer for 3.0 h, plus tetrahydrofuran solvent, and pressed with a strength of 10 tons/cm2. The material produced was analysis using Scanning Electron Microscopy (SEM), voltammetry potential V and Tafel plot. The material is used as an electrode for the determination of uric acid and the synthesis of acetic acid from ethanol. The results showed that Pt-PCM has evenly distributed pores and has a perfect Tafel slope compared to metal platinum or solid platinum. Pt-PCM also has the excellent ability as a working electrode for the analysis of uric acid in human urine and electro synthetic acetic acid from alcohol. In conclusion, Pt-Porous Composite Material (Pt-PCM) is a porous material, so it is excellent as a candidate for electrodes.