Molecular Pathophysiology of Gout

Desai, Jyaysi; Steiger, Stefanie; Anders, Hans‐Joachim

doi:10.1016/j.molmed.2017.06.005

Cited by 180 publications

(143 citation statements)

References 105 publications

Supporting

Mentioning

125

Contrasting

Order By: Relevance

“…Gout pathogenesis begins with excess serum urate that forms monosodium urate crystals in the joints, triggering gouty inflammation via the activation of nucleotide-binding and oligomerization domainelike receptor, leucine-rich repeat and pyrin domainecontaining 3 (NLRP3) inflammasome-mediated IL-1b production [8,9]. The standard therapeutic diet for gout prevention and management focuses on restriction of purine e a substrate metabolized to urate and contributes to one-third of total urate pool [10] e has only a moderate urate-lowering effect that most clinicians regard as insufficient [11].…”

Section: Introductionmentioning

confidence: 99%

Vegetarian diet and risk of gout in two separate prospective cohort studies

et al. 2020

View full text Add to dashboard Cite

Backgrounds & aims: Plant-based diets may target multiple pathways in gout pathogenesis (uric acid reduction and anti-inflammation) while improving gout associated cardiometabolic comorbidities. We aim to prospectively examine the relationship between a vegetarian diet and gout, and to explore if this relationship is independent of hyperuricemia. Methods: We followed 4903 participants in the Tzu Chi Health Study (Cohort1, recruited in 2007e2009) and 9032 participants in the Tzu Chi Vegetarian Study (Cohort2, recruited in 2005) until end of 2014. Baseline serum uric acid was measured in Cohort1. Vegetarian status was assessed through a diet questionnaire that includes dietary habits and a food frequency questionnaire. Incidence of gout was ascertained by linkage to the National Health Insurance Database. Hazard Ratio of gout in vegetarians versus nonvegetarians was assessed by Cox regression, adjusted for age, sex, lifestyle and metabolic risk factors. Hyperuricemia was additionally adjusted in Cohort1. Results: In Cohort1, lacto-ovo vegetarians had the lowest uric acid concentration, followed by vegans, then nonvegetarians (men: 6.05, 6.19, 6.32 mg/dL, respectively; women: 4.92, 4.96, 5.11 mg/dL, respectively); 65 gout cases occurred in the 29,673 person-years of follow-up; vegetarians experienced a lower risk of gout (without adjustment for hyperuricemia: HR: 0.33; 95% CI: 0.14, 0.79; with adjustment for hyperuricemia: HR: 0.40; 95% CI: 0.17, 0.97). In Cohort2, 161 gout cases occurred in the 83,019 personyears follow-up, and vegetarians also experienced a lower risk of gout (HR: 0.61; 95% CI: 0.41, 0.88). Conclusion: Taiwanese vegetarian diet is associated with lower risk of gout. This protective association may be independent of baseline hyperuricemia.

show abstract

Section: Introductionmentioning

confidence: 99%

Vegetarian diet and risk of gout in two separate prospective cohort studies

et al. 2020

View full text Add to dashboard Cite

show abstract

“…MSU crystal-induced intracellular signaling generates acute joint inflammation and mediates neutrophil migration and activation (6). The progression of sterile inflammation in acute gouty arthritis is promoted by an auto-amplification loop of the inflammation (7).…”

Section: Introductionmentioning

confidence: 99%

1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Mitigates Monosodium Urate (MSU)-Induced Acute Gouty Inflammation in BALB/c Mice

et al. 2020

View full text Add to dashboard Cite

Acute gouty arthritis is an auto-inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in joints or tissues. Excessive neutrophil recruitment into gouty lesions is a general clinical sign and induces a pain phenotype. Attenuation of successive periods of neutrophil infiltration might be a beneficial approach to achieve therapeutic efficacy. In this study, the activity of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) in attenuation of excess neutrophil infiltration was assessed in gout-induced lesions of BALB/c mice. Neutrophil infiltration in MSU-induced gouty lesions was analyzed using immunohistochemical staining. ELISA and RT-PCR were used to measure attenuation of expression of the major neutrophil chemoattractant, CXC motif chemokine ligand 8 (CXCL8), in a PLAG-treated animal model and in cells in vitro. The animal model revealed massive increased neutrophil infiltration in the MSU-induced gouty lesions, but the PLAG-treated mice had significantly reduced neutrophil numbers in these lesions. The results also indicated that the MSU crystals stimulated a damage-associated molecular pattern that was recognized by the P2Y6 purinergic receptor. This MSU-stimulated P2Y6 receptor was destined to intracellular trafficking. During intracellular endosomal trafficking of the receptor, endosome-dependent signaling provided expression of CXCL8 chemokines for neutrophil recruitment. PLAG accelerated initiation of the intracellular trafficking of the P2Y6 receptor and returning the receptor to the membrane. This process shortened the intracellular retention time of the receptor anchoring endosome and subsequently attenuated endosome-dependent signaling for CXCL8 expression. These study results suggested that PLAG could be used for resolution of acute inflammation induced in gout lesions.

show abstract

“…However, the antioxidant capacity of UA is overshadowed by detrimental effects when its concentration exceeds its maximal solubility (6-7 mg/dl) [4]. In this scenario, UA precipitates and crystalizes as monosodium urate (MSU), which gets deposited in joints, leading to inflammation and gouty arthritis [5]. Since there is an overlap in UA concentrations that define hyperuricemia and that dictate MSU crystal formation, and both have pathological implications, recent discussions continue to emphasize the need for reduction in this 'healthy' UA range [3].…”

Section: Introductionmentioning

confidence: 99%

Hereditary hemochromatosis disrupts uric acid homeostasis and causes hyperuricemia via altered expression/activity of xanthine oxidase and ABCG2

Ristić

Sivaprakasam

Narayanan

et al. 2020

Biochemical Journal

View full text Add to dashboard Cite

Hereditary hemochromatosis (HH) is mostly caused by mutations in the iron-regulatory gene HFE. The disease is associated with iron overload, resulting in liver cirrhosis/cancer, cardiomegaly, kidney dysfunction, diabetes, and arthritis. Fe2+-induced oxidative damage is suspected in the etiology of these symptoms. Here we examined, using Hfe−/− mice, whether disruption of uric acid (UA) homeostasis plays any role in HH-associated arthritis. We detected elevated levels of UA in serum and intestine in Hfe−/− mice compared with controls. Though the expression of xanthine oxidase, which generates UA, was not different in liver and intestine between wild type and Hfe−/− mice, the enzymatic activity was higher in Hfe−/− mice. We then examined various transporters involved in UA absorption/excretion. Glut9 expression did not change; however, there was an increase in Mrp4 and a decrease in Abcg2 in Hfe−/− mice. As ABCG2 mediates intestinal excretion of UA and mutations in ABCG2 cause hyperuricemia, we examined the potential connection between iron and ABCG2. We found p53-responsive elements in hABCG2 promoter and confirmed with chromatin immunoprecipitation that p53 binds to this promoter. p53 protein was reduced in Hfe−/− mouse intestine. p53 is a heme-binding protein and p53-heme complex is subjected to proteasomal degradation. We conclude that iron/heme overload in HH increases xanthine oxidase activity and also promotes p53 degradation resulting in decreased ABCG2 expression. As a result, systemic UA production is increased and intestinal excretion of UA via ABCG2 is decreased, causing serum and tissue accumulation of UA, a potential factor in the etiology of HH-associated arthritis.

show abstract

Molecular Pathophysiology of Gout

Cited by 180 publications

References 105 publications

Vegetarian diet and risk of gout in two separate prospective cohort studies

Vegetarian diet and risk of gout in two separate prospective cohort studies

1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Mitigates Monosodium Urate (MSU)-Induced Acute Gouty Inflammation in BALB/c Mice

Hereditary hemochromatosis disrupts uric acid homeostasis and causes hyperuricemia via altered expression/activity of xanthine oxidase and ABCG2

Contact Info

Product

Resources

About