Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, China; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Hangzhou, 310006, China; Institute of Drug Metabolism and Pharmaceutical Analysis, Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Institute of Drug Metabolism and Pharmaceutical Analysis, Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Free Radic Biol Med. 2024 Nov 1;224:644-659. doi: 10.1016/j.freeradbiomed.2024.09.023. Epub 2024 Sep 18.
Hyperuricemia and its development to gout have reached epidemic proportions. Systemic hyperuricemia is facilitated by elevated activity of xanthine oxidase (XO), the sole source of uric acid in mammals. Here, we aim to investigate the role of bilirubin in maintaining circulating uric acid homeostasis. We observed serum bilirubin concentrations were inversely correlated with uric acid levels in humans with new-onset hyperuricemia and advanced gout in a clinical cohort consisting of 891 participants. We confirmed that bilirubin biosynthesis impairment recapitulated traits of hyperuricemia symptoms, exemplified by raised circulating uric acid levels and accumulated hepatic XO, and exacerbated mouse hyperuricemia development. Bilirubin administration significantly decreased circulating uric acid levels in hyperuricemia-inducing (HUA) mice receiving potassium oxonate (a uricase inhibitor) or fed with a high fructose diet. Finally, we proved that bilirubin ameliorated mouse hyperuricemia by increasing hepatic autophagy, restoring antioxidant defense and normalizing mitochondrial function in a manner dependent on AMPK pathway. Hepatocyte-specific AMPKα knockdown via adeno-associated virus (AAV) 8-TBG-mediated gene delivery compromised the efficacy of bilirubin in HUA mice. Our study demonstrates the deficiency of bilirubin in hyperuricemia progression, and the protective effects exerted by bilirubin against mouse hyperuricemia development, which may potentiate clinical management of hyperuricemia.
高尿酸血症及其发展为痛风已达到流行程度。黄嘌呤氧化酶 (XO) 的活性升高促进了全身高尿酸血症，XO 是哺乳动物尿酸的唯一来源。在这里，我们旨在研究胆红素在维持循环尿酸稳态中的作用。我们观察到，在一个由 891 名参与者组成的临床队列中，新发高尿酸血症和进展性痛风患者的血清胆红素浓度与尿酸水平呈负相关。我们证实胆红素生物合成障碍再现了高尿酸血症症状的特征，表现为循环尿酸水平升高和肝 XO 积累，并加重了小鼠高尿酸血症的发展。胆红素给药可显著降低接受黄嘌呤氧化酶抑制剂氧嗪酸钾或高果糖饮食诱导的高尿酸血症 (HUA) 小鼠的循环尿酸水平。最后，我们证明胆红素通过增加肝自噬、恢复抗氧化防御和使线粒体功能正常化，在依赖 AMPK 途径的方式下，改善了小鼠高尿酸血症。通过腺相关病毒 (AAV) 8-TBG 介导的基因传递对肝特异性 AMPKα 的敲低削弱了胆红素在 HUA 小鼠中的疗效。我们的研究表明胆红素在高尿酸血症进展中的缺乏，以及胆红素对小鼠高尿酸血症发展的保护作用，这可能增强高尿酸血症的临床管理。
