Xanthine Oxidase Inhibition Attenuates Insulin Resistance and Diet-Induced Steatohepatitis in Mice

Nishikawa, Tomoki; Nagata, Naoto; Shimakami, Tetsuro; Saito, Takashi; Matsui, Chieko; Ota, Tsuguhito; Zhuge, Fen; Xu, Liang; Chen, Guanliang; Nagashimada, Mayumi; Yamashita, Taro; Sakai, Yoshio; Yamashita, Tatsuya; Mizukoshi, Eishiro; Honda, Masao; Kaneko, Shuichi; Ota, Tsuguhito

doi:10.2139/ssrn.3391355

Cited by 9 publications

(14 citation statements)

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“…Xanthine oxidase converts molecular oxygen to superoxide anion or hydrogen peroxide [ 3 ]. As XO is a major contributor to oxidative stress, the enzyme inhibitors are actively studied as therapeutic agents in pathologies accompanied by oxidative stress development [ 13 , 14 ].…”

Section: Redox System In Health and Disease: Brief Overviewmentioning

confidence: 99%

The Universal Soldier: Enzymatic and Non-Enzymatic Antioxidant Functions of Serum Albumin

et al. 2020

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As a carrier of many biologically active compounds, blood is exposed to oxidants to a greater extent than the intracellular environment. Serum albumin plays a key role in antioxidant defence under both normal and oxidative stress conditions. This review evaluates data published in the literature and from our own research on the mechanisms of the enzymatic and non-enzymatic activities of albumin that determine its participation in redox modulation of plasma and intercellular fluid. For the first time, the results of numerous clinical, biochemical, spectroscopic and computational experiments devoted to the study of allosteric modulation of the functional properties of the protein associated with its participation in antioxidant defence are analysed. It has been concluded that it is fundamentally possible to regulate the antioxidant properties of albumin with various ligands, and the binding and/or enzymatic features of the protein by changing its redox status. The perspectives for using the antioxidant properties of albumin in practice are discussed.

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Section: Redox System In Health and Disease: Brief Overviewmentioning

confidence: 99%

The Universal Soldier: Enzymatic and Non-Enzymatic Antioxidant Functions of Serum Albumin

et al. 2020

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“…In addition, c-Jun N-terminal kinase (JNK) is a protein kinase that is activated in response to oxidative stress. XOR activity induces oxidative stress and activates JNK, and the activated JNK has been reported to inhibit insulin signaling and induce hepatic steatosis [39,40].…”

Section: Discussionmentioning

confidence: 99%

Xanthine Oxidoreductase Activity Is Correlated With Hepatic Steatosis

Yagi¹,

Kusunoki²,

Tsunoda³

et al. 2021

Preprint

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The enzyme xanthine oxidoreductase (XOR) catalyzes the formation of uric acid (UA) from hypoxanthine and xanthine, which in turn are products of purine metabolism starting from ribose-5-phosphate. Several studies suggested a relationship between hyperuricemia and hepatic steatosis; however, few previous studies have directly examined the relationship between XOR and hepatic steatosis. A total of 223 subjects with one or more cardiovascular risk factors were enrolled. Hepatic steatosis was calculated according to the liver-to-spleen (L/S) ratio on computed tomography and the hepatic steatosis index (HSI). We measured a plasma XOR activity assay using a newly established highly sensitive assay based on [13C2, 15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. XOR activity and the UA level were increased in subjects with L/S ratio <1.1 and HSI <36. Multivariate logistic regression analysis indicated that plasma XOR activity was associated with the risk of hepatic steatosis as assessed by the L/S ratio and HSI independently of insulin resistance, whereas UA levels were not associated with risk of hepatic steatosis. The results of this study indicated that plasma XOR activity is associated with hepatic steatosis independently of insulin resistance and serum UA levels.

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“…(IV) Frequent use of xanthine oxidase (XO) inhibition provides the potential to attenuate liver damage. Recent evidence indicated that XO inhibition could attenuate diet-induced steatohepatitis in mice [65,66]. Specially, febuxostat, with its non-purine structure, selectively inhibits both the oxidized and reduced form of XO [67], has been shown to signi cantly decrease hepatic XO activity and UA levels in the NAFLD model mice, accompanied by attenuation of insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver [65].…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence indicated that XO inhibition could attenuate diet-induced steatohepatitis in mice [65,66]. Specially, febuxostat, with its non-purine structure, selectively inhibits both the oxidized and reduced form of XO [67], has been shown to signi cantly decrease hepatic XO activity and UA levels in the NAFLD model mice, accompanied by attenuation of insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver [65]. Experts further found that in NAFLD patients with hyperuricemia, treatment with febuxostat for 24 weeks signi cantly decreased the serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase.…”

Section: Discussionmentioning

confidence: 99%

The Negative Association Between Non-alcoholic Fatty Liver Disease Severity and Gouty Nephropathy in a Non-diabetic Gouty Population: A Cross-Sectional Study

Zhou¹,

Wang²,

Chi³

et al. 2020

Preprint

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Background: Nonalcoholic fatty liver (NAFLD) and chronic kidney disease (CKD) share common pathogenic mechanisms and risk factors, but the specific relationship between NAFLD and gouty nephropathy has not been well understood. We aim to evaluate the association between NAFLD and gouty nephropathy in a non-diabetic gouty population.Methods: The retrospective cross‑sectional study was performed on 1049 non-diabetic gouty participants, who were hospitalized between 2014 and 2020, across 4 districts in Shandong, China. Demographic and clinical characteristics of the study population were collected. The odds ratios (OR) and corresponding 95% confidence intervals (CI) in relation to the NAFLD severity determined by ultrasonography were obtained by multiple logistic regression analysis. Results: An unexpectedly inverse relationship was found between NAFLD severity and the risk of gout nephropathy. Multivariate logistic regression analysis demonstrated that higher degree of NAFLD severity is independently associated with lower risk of gouty nephropathy, after adjusted for age, sex, smoking, gout duration, and metabolic risk factors including obesity, hypertension, hyperglycemia, hyperuriacemia and dyslipidemia, with OR 0.392 (95 % CI 0.248–0.619, P < 0.001), 0.379 (95 % CI 0.233–0.616, P < 0.001) and 0.148 (95 % CI 0.043–0.512, P = 0.003) in participants with mild, moderate, and severe NAFLD, respectively, compared to those without NAFLD. We also observed a weakened association of serum uric acid (SUA) with metabolic risk factors and NAFLD under circumstances of gouty nephropathy (r = -0.054, P = 0.466). Conclusions: The presence and severity of NAFLD was negatively associated with the risk of gouty nephropathy in the non-diabetic gouty populations. Further investigation of NAFLD will provide insights into the pathogenesis of gouty nephropathy.Trials registration: Chinese Clinical Trials Registry ChiCTR2000035185. Registered 2 August 2020.

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Xanthine Oxidase Inhibition Attenuates Insulin Resistance and Diet-Induced Steatohepatitis in Mice

Cited by 9 publications

References 0 publications

The Universal Soldier: Enzymatic and Non-Enzymatic Antioxidant Functions of Serum Albumin

The Universal Soldier: Enzymatic and Non-Enzymatic Antioxidant Functions of Serum Albumin

Xanthine Oxidoreductase Activity Is Correlated With Hepatic Steatosis

The Negative Association Between Non-alcoholic Fatty Liver Disease Severity and Gouty Nephropathy in a Non-diabetic Gouty Population: A Cross-Sectional Study

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