Thyroid Hormone-Regulated Expression of Period2 Promotes Liver Urate Production

Objective: The relationship between thyroid hormones and serum urate is unclear. Our aim is to analyze the correlation between uric acid and thyroid hormones in gout patients and to explore the effect and mechanism of triiodothyronine on liver uric acid production. Methods: Eighty men patients with gout were selected to analyze the correlation between blood urate and thyroid function-related hormone levels. Stepwise multiple linear regression was used to analyze factors affecting blood urate in patients with gout. Levels of urate in serum, liver, and cell culture supernatant were measured after triiodothyronine treatment. Purine levels (adenine, guanine and hypoxanthine) were also measured. Expression levels of Period2 and nucleotide metabolism enzymes were analyzed after triiodothyronine treatment and Period2-shRNA lentivirus transduction. Chromatin immunoprecipitation was used to analyze the effects of triiodothyronine and thyroid hormone receptor-β on Period2 expression. Results: Correlation and regression analyses of clinical samples showed that free T3 influenced the serum urate level. Furthermore, urate levels increased in mouse liver and cell culture supernatant following treatment with triiodothyronine. Purine levels in mouse liver increased, accompanied by upregulation of enzymes involved in nucleotide metabolism. These phenomena were reversed in Period2 knockout mice. Triiodothyronine promoted the binding of thyroid hormone receptor-β to the Period2 promoter and subsequent transcription of Period2. Triiodothyronine also enhanced nuclear expression of Sirt1, which synergistically enhanced Period2 expression. Conclusion: The study demonstrated that T3 is independently positively correlated with serum urate and liver uric acid production through Period2, providing novel insights into the purine metabolism underlying hyperuricemia/gout pathophysiology. Funding Statement: This work was supported by National Key R＆D Program of China, Synthetic Biology Research [grant number 2019YFA0904500] and the National Natural Science Foundation of China [grant numbers 81670737, 81870616]. Declaration of Interests: None declared. Ethics Approval Statement: The study was approved by the Ethics Committee of the Sixth People's Hospital affiliated to Shanghai Jiaotong University (Approval No: 2018-102). All experiments were approved by the animal experimentation committee of the Sixth People's Hospital affiliated to Shanghai Jiaotong University (Approval No: 2020-0088).