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Unconjugated bilirubin promotes uric acid restoration by activating hepatic AMPK pathway.
Zhang, Yingqiong; Chen, Yujia; Chen, Xiaojing; Gao, Yue; Luo, Jun; Lu, Shuanghui; Li, Qi; Li, Ping; Bai, Mengru; Jiang, Ting; Zhang, Nanxin; Zhang, Bichen; Chen, Binxin; Zhou, Hui; Jiang, Huidi; Lin, Nengming.
Afiliación
  • Zhang Y; 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 Pharmac
  • Chen Y; Institute of Drug Metabolism and Pharmaceutical Analysis, Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • Chen X; Department of Endocrinology, the Third People's Hospital of Yuhang District, Hangzhou, 311115, China.
  • Gao Y; Zhejiang Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment of Senile Chronic Diseases, Hangzhou First People's Hospital, Hangzhou, 310006, China.
  • Luo J; Institute of Drug Metabolism and Pharmaceutical Analysis, Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • Lu S; Institute of Drug Metabolism and Pharmaceutical Analysis, Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • Li Q; 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.
  • Li P; 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 Univer
  • Bai M; Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Hangzhou, 310006, China.
  • Jiang T; Institute of Drug Metabolism and Pharmaceutical Analysis, Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • Zhang N; Institute of Drug Metabolism and Pharmaceutical Analysis, Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • Zhang B; Institute of Drug Metabolism and Pharmaceutical Analysis, Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • Chen B; 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 Pharmac
  • Zhou H; Institute of Drug Metabolism and Pharmaceutical Analysis, Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • Jiang H; Institute of Drug Metabolism and Pharmaceutical Analysis, Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. Electronic address: hdjiang@zju.edu.cn.
  • Lin N; 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; Westlake Laboratory of Life Sciences and
Free Radic Biol Med ; 2024 Sep 17.
Article en En | MEDLINE | ID: mdl-39299526
ABSTRACT
Hyperuricemia and its development to gout have reached epidemic proportions. Systemic hyperuricemia is facilitated by elevated activity of xanthine oxidase, 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 xanthine oxidase, 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 xanthine oxidase autophagic degradation, 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Free Radic Biol Med Asunto de la revista: BIOQUIMICA / MEDICINA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Free Radic Biol Med Asunto de la revista: BIOQUIMICA / MEDICINA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos