Author ORCID Identifier

https://orcid.org/0000-0002-6906-7831

Semester

Spring

Date of Graduation

2025

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Biochemistry

Committee Chair

Michael Gunther

Committee Co-Chair

Eric Kelley

Committee Member

Eric Kelley

Committee Member

Elizabeth Bowdridge

Committee Member

Bradley Webb

Committee Member

Jianhai Du

Abstract

Chronic elevated circulating uric acid (UA) levels (hyperuricemia) are associated with gout as well as cardiovascular, metabolic, and renal dysfunction. Men have greater mean circulating UA levels than women and are more likely to exhibit hyperuricemia. This may be partly driven by the hormonal regulation of renal UA transporters; however, a direct link between hormones and UA production has not been established. Production of UA is catalyzed by xanthine oxidoreductase (XOR / XDH), which is ubiquitously expressed but has the greatest specific activity in the liver. Interestingly, an extensive gout genome-wide association study (GWAS) recently revealed a robust genetic association between sequence variants via single-nucleotide polymorphism (SNPs) at the XDH locus and gout in men versus women. Surprisingly, these SNPs were associated with elevated mRNA expression of XDH and UA transporters in the prostate and not the liver. In addition, reports demonstrate potential hormonal (testosterone/estrogen) regulation of urate transporters, XOR expression, and UA production. When taken together, these observations incentivized our hypothesis that the prostate, in conjunction with hormonal input, may contribute to the greater levels of circulating UA in men versus women. To test this hypothesis, we used a preclinical murine model and revealed that the prostate contains similar levels of XOR and UA as the liver (XOR or UA/mg protein). In addition, when castrated, male mice demonstrate diminution in both XOR and UA levels by 4 weeks, which is recovered by 8 weeks, indicating compensation by alternative tissue(s). Furthermore, genetic ablation (50%) of XOR in prostate epithelial cells did not alter circulating UA levels. In the aggregate, these data do not support our hypothesis; however, they do not discount the possibility that both prostate-specific UA production and hormonal regulation of XOR may synergize to impact overall plasma UA levels in men and serve to incentivize future work in that direction.

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