Increased plasma XOR activity induced by NAFLD/NASH and its possible involvement in vascular neointimal proliferation

Kawachi, Yusuke; Fujishima, Yuya; Nishizawa, Hitoshi; Nakamura, Takashi; Akari, Seigo; Murase, Takayo; Saito, Takuro; Miyazaki, Yasuhiro; Nagao, Hirofumi; Fukuda, Shiro; Kita, Satomi; Katakami, Naoto; Doki, Yuichiro; Maeda, Norikazu; Shimomura, Iichiro

doi:10.1172/jci.insight.144762

Cited by 19 publications

(13 citation statements)

References 49 publications

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“…Our previous studies in both humans and mice demonstrated that increased plasma XOR activity was directly induced by liver damage, together with increases in liver enzymes such as serum ALT and AST. Moreover, high XOR in liver disease conditions accelerated purine catabolism in the plasma per se using hypoxanthine secreted from vascular endothelial cells or adipocytes as substrate, which was accompanied by the development of vascular endothelial injury and neointimal proliferation [ 11 , 12 , 13 ]. Additionally, a cross-sectional study by another group reported a significant positive correlation between plasma XOR activity and CAVI in patients with type 2 diabetes and liver dysfunction [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…Human XOR expression is detected mainly in liver, lungs, and gut [ 11 ]. Recently, we reported that circulating XOR in humans and mice markedly increased with elevations in liver enzymes such as serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST), reflecting excessive leakage of hepatic XOR, and that topiroxostat, a selective XOR inhibitor, suppressed plasma XOR activity and attenuated the development of vascular neointima formation in a diet-induced mouse model of NAFLD/NASH [ 12 , 13 ]. Therefore, we hypothesize that XOR inhibitors may have the potential to prevent or delay cardiovascular complications, especially in patients with liver dysfunction, possibly beyond their UA-lowering effect.…”

Section: Introductionmentioning

confidence: 99%

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The Effects of Topiroxostat, a Selective Xanthine Oxidoreductase Inhibitor, on Arterial Stiffness in Hyperuricemic Patients with Liver Dysfunction: A Sub-Analysis of the BEYOND-UA Study

et al. 2023

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Background: The effects of uric acid (UA)-lowering therapy with xanthine oxidoreductase (XOR) inhibitors on the development of cardiovascular diseases remain controversial. Based on recent findings that plasma XOR activity increased in liver disease conditions, we conducted a sub-analysis of the BEYOND-UA study to examine the differential effects of topiroxostat on arterial stiffness based on liver function in hyperuricemic individuals with hypertension. Methods: Sixty-three subjects treated with topiroxostat were grouped according to baseline alanine aminotransferase (ALT) levels (above or below cut-off values of 22, 30, or 40 U/L). The primary endpoint was changes in the cardio-ankle vascular index (CAVI) from baseline to 24 weeks. Results: Significant reductions in CAVI during topiroxostat therapy occurred in subjects with baseline ALT ≥30 U/L or ≥40 U/L, and significant between-group differences were detected. Brachial-ankle pulse wave velocity significantly decreased in the ALT-high groups at all cut-off values. Reductions in morning home blood pressure and serum UA were similar regardless of the baseline ALT level. For eleven subjects with available data, ALT-high groups showed high plasma XOR activity, which was significantly suppressed by topiroxostat. Conclusions: Topiroxostat improved arterial stiffness parameters in hyperuricemic patients with liver dysfunction, which might be related to its inhibitory effect on plasma XOR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Effects of Topiroxostat, a Selective Xanthine Oxidoreductase Inhibitor, on Arterial Stiffness in Hyperuricemic Patients with Liver Dysfunction: A Sub-Analysis of the BEYOND-UA Study

et al. 2023

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“…Higher hypoxanthine levels were associated with obesity and were secreted from adipose tissues under hypoxic conditions [ 38 , 39 ]. Increase in plasma XOR activity was induced by the disease [ 40 ]. The decrease in xanthine levels with the improvement in liver fat can be explained by the fact that ezetimibe attenuates steatohepatitis through the induction of autophagy and the inhibition of NLRP3 inflammasome [ 41 ] which would result in the downregulation of the purine catabolism pathway.…”

Section: Discussionmentioning

confidence: 99%

Association of Metabolomic Change and Treatment Response in Patients with Non-Alcoholic Fatty Liver Disease

et al. 2022

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Non-alcoholic fatty liver disease (NAFLD) is the major cause of chronic liver disease, yet cost-effective and non-invasive diagnostic tools to monitor the severity of the disease are lacking. We aimed to investigate the metabolomic changes in NAFLD associated with therapeutic responses. It was conducted in 63 patients with NAFLD who received either ezetimibe plus rosuvastatin or rosuvastatin monotherapy. The treatment response was determined by MRI performed at baseline and week 24. The metabolites were measured at baseline and week 12. In the combination group, a relative decrease in xanthine was associated with a good response to liver fat decrease, while a relative increase in choline was associated with a good response to liver stiffness. In the monotherapy group, the relative decreases in triglyceride (TG) 20:5_36:2, TG 18:1_38:6, acetylcarnitine (C2), fatty acid (FA) 18:2, FA 18:1, and docosahexaenoic acid were associated with a decrease in liver fat, while hexosylceramide (d18:2/16:0) and hippuric acid were associated with a decrease in liver stiffness. Models using the metabolite changes showed an AUC of >0.75 in receiver operating curve analysis for predicting an improvement in liver fat and stiffness. This approach revealed the physiological impact of drugs, suggesting the mechanism underlying the development of this disease.

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“…The main role in the formation of UA is purines, and the accumulation of purines in the body is the main reason for the production of HUA. XO is the critical enzyme in the last step of UA synthesis, which catalyzes the oxidation of hypoxanthine to xanthine and then to UA, or directly to UA ( Furuhashi et al, 2018 ; Kawachi et al, 2021 ). Several studies have shown that flavonoids ( Scheepers et al, 2019 ) and saponins ( Xu et al, 2022 ) isolated from TCM can reduce UA by reducing the content of XO in the liver while enhancing renal excretion of UA.…”

Section: Discussionmentioning

confidence: 99%

Improved effect of fresh ginseng paste (radix ginseng-ziziphus jujube) on hyperuricemia based on network pharmacology and molecular docking

Zhang

Liu²,

Qi³

et al. 2022

Front. Pharmacol.

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Background: Hyperuricemia (HUA) is a metabolic disease caused by reduced excretion or increased production of uric acid. This research aims to study the practical components, active targets, and potential mechanism of the “Radix ginseng (RG)-Ziziphus jujube (ZJ)” herb pair through molecular docking, network pharmacology, and animal experiments.Methods: The potential targets of “Radix ginseng (RG)-Ziziphus jujube (ZJ)” herb pair were obtained from the TCMSP database. The therapeutic targets of HUA were acquired from the GendCards, OMIM, PharmGkb, and TTD databases. Protein-protein interaction network (PPI) was constructed in the STRING 11.0 database. The David database was used for enrichment analysis. Molecular Docking was finished by the AutoDock Vina. And we employed Radix ginseng and Ziziphus jujube as raw materials, which would develop a new functional food fresh ginseng paste (FGP) after boiling. In addition, benzbromarone (Ben) (7.8 mg/kg) and allopurinol (All) (5 mg/kg) were used as positive drugs to evaluate the hyperuricemia induced by FGP (400 and 800 mg/kg) potassium oxazine (PO) (100 mg/kg) and hypoxanthine (HX) (500 mg/kg) on mice.Results: The results showed that 25 targets in the “RG-ZJ” herb pair interacted with hyperuricemia. Then protein-protein interaction (PPI) analysis showed that TNF, IL-1β, and VEGFA were core genes. KEGG enrichment analysis showed that the Toll-like receptor signaling pathway and IL-17 signaling pathway were mainly involved. Meantime, animal experiments showed that FGP could improve the HUA status of mice by reducing serum UA BUN, XO, and liver XO levels (p < 0.05, p < 0.01). Furthermore, we analyzed the main ingredients of FGP by HPLC. We found that the main ingredients of FGP had solid binding activity to the core target of HUA by molecular docking.Conclusion: This study explored the active ingredients and targets of the “RG-ZJ” herb pair on HUA through network pharmacology, molecular docking, and animal experiments. It revealed the improvement of FGP in mice with HUA.

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Increased plasma XOR activity induced by NAFLD/NASH and its possible involvement in vascular neointimal proliferation

Cited by 19 publications

References 49 publications

The Effects of Topiroxostat, a Selective Xanthine Oxidoreductase Inhibitor, on Arterial Stiffness in Hyperuricemic Patients with Liver Dysfunction: A Sub-Analysis of the BEYOND-UA Study

The Effects of Topiroxostat, a Selective Xanthine Oxidoreductase Inhibitor, on Arterial Stiffness in Hyperuricemic Patients with Liver Dysfunction: A Sub-Analysis of the BEYOND-UA Study

Association of Metabolomic Change and Treatment Response in Patients with Non-Alcoholic Fatty Liver Disease

Improved effect of fresh ginseng paste (radix ginseng-ziziphus jujube) on hyperuricemia based on network pharmacology and molecular docking

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