Slow Metabolism–Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone‐Induced Obesity‐Specific Liver Injury
Abstract Obesity and nonalcoholic fatty liver disease (NAFLD) are established risk factors for drug‐induced liver injury (DILI). The previous study demonstrates that benzbromarone (BBR), a commonly prescribed pharmaceutical agent for managing gout and hyperuricemia, exacerbates hepatic steatosis and...
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202409126 |
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| author | Guanting Li Yourong Hu Han Zhao Ziyu Peng Xin Shang Jia Zhang Kunxin Xie Meiwei Li Xiaohang Zhou Qinyao Zhou Kai Li Fang Zhou Heyao Wang Zhijian Xu Jiali Liu Peng Sun |
| author_facet | Guanting Li Yourong Hu Han Zhao Ziyu Peng Xin Shang Jia Zhang Kunxin Xie Meiwei Li Xiaohang Zhou Qinyao Zhou Kai Li Fang Zhou Heyao Wang Zhijian Xu Jiali Liu Peng Sun |
| author_sort | Guanting Li |
| collection | DOAJ |
| description | Abstract Obesity and nonalcoholic fatty liver disease (NAFLD) are established risk factors for drug‐induced liver injury (DILI). The previous study demonstrates that benzbromarone (BBR), a commonly prescribed pharmaceutical agent for managing gout and hyperuricemia, exacerbates hepatic steatosis and liver injury specifically in obese individuals. However, the precise mechanism underpinning this adverse effect remains incompletely elucidated. Given the significance of BBR and its analogs in anti‐gout/hyperuricemia drug discovery, elucidating the mechanism by which BBR exacerbates obesity‐specific DILI warrants further investigation. In this study, through a combined multi‐omics, pharmacological, and pharmacokinetic approaches, it is found that BBR‐induced obesity‐specific DILI is primarily through the potentiation of peroxisome proliferator‐activated receptor gamma (PPARγ) signaling pathways. Further in vivo and in vitro pharmacokinetic analyses reveal that obese db/db mice exhibited a diminished capacity to metabolize BBR in their livers. This reduction leads to prolonged retention of BBR, subsequently resulting in chronic and sustained hepatic PPARγ agonism. This study demonstrates that a slow metabolism‐driven amplification of hepatic PPARγ agonism mediates BBR‐induced obesity‐specific hepatic steatosis and subsequent DILI, which also emphasizes the importance of the reduced hepatic drug metabolism capacity in patients with obesity or pre‐existing NAFLD in both clinical practice and drug discovery processes. |
| format | Article |
| id | doaj-art-d061fd3c93e7432791c05b1d04e8f70f |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-d061fd3c93e7432791c05b1d04e8f70f2025-01-20T13:04:19ZengWileyAdvanced Science2198-38442025-01-01123n/an/a10.1002/advs.202409126Slow Metabolism–Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone‐Induced Obesity‐Specific Liver InjuryGuanting Li0Yourong Hu1Han Zhao2Ziyu Peng3Xin Shang4Jia Zhang5Kunxin Xie6Meiwei Li7Xiaohang Zhou8Qinyao Zhou9Kai Li10Fang Zhou11Heyao Wang12Zhijian Xu13Jiali Liu14Peng Sun15The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Key Laboratory of Human Functional Genomics of Jiangsu Province Department of Biochemistry and Molecular Biology Nanjing Medical University Nanjing 211166 ChinaThe Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Key Laboratory of Human Functional Genomics of Jiangsu Province Department of Biochemistry and Molecular Biology Nanjing Medical University Nanjing 211166 ChinaThe Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Key Laboratory of Human Functional Genomics of Jiangsu Province Department of Biochemistry and Molecular Biology Nanjing Medical University Nanjing 211166 ChinaState Key Laboratory of Drug Research Drug Discovery and Design Center Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 ChinaKey Laboratory of Drug Metabolism and Pharmacokinetics State Key Laboratory of Natural Medicines China Pharmaceutical University Nanjing 210009 ChinaThe Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Key Laboratory of Human Functional Genomics of Jiangsu Province Department of Biochemistry and Molecular Biology Nanjing Medical University Nanjing 211166 ChinaThe Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Key Laboratory of Human Functional Genomics of Jiangsu Province Department of Biochemistry and Molecular Biology Nanjing Medical University Nanjing 211166 ChinaThe Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Key Laboratory of Human Functional Genomics of Jiangsu Province Department of Biochemistry and Molecular Biology Nanjing Medical University Nanjing 211166 ChinaThe Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Key Laboratory of Human Functional Genomics of Jiangsu Province Department of Biochemistry and Molecular Biology Nanjing Medical University Nanjing 211166 ChinaThe Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Key Laboratory of Human Functional Genomics of Jiangsu Province Department of Biochemistry and Molecular Biology Nanjing Medical University Nanjing 211166 ChinaThe Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Key Laboratory of Human Functional Genomics of Jiangsu Province Department of Biochemistry and Molecular Biology Nanjing Medical University Nanjing 211166 ChinaKey Laboratory of Drug Metabolism and Pharmacokinetics State Key Laboratory of Natural Medicines China Pharmaceutical University Nanjing 210009 ChinaState Key Laboratory of Drug Research Drug Discovery and Design Center Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 ChinaState Key Laboratory of Drug Research Drug Discovery and Design Center Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 ChinaKey Laboratory of Drug Metabolism and Pharmacokinetics State Key Laboratory of Natural Medicines China Pharmaceutical University Nanjing 210009 ChinaThe Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi People's Hospital Wuxi Medical Center Key Laboratory of Human Functional Genomics of Jiangsu Province Department of Biochemistry and Molecular Biology Nanjing Medical University Nanjing 211166 ChinaAbstract Obesity and nonalcoholic fatty liver disease (NAFLD) are established risk factors for drug‐induced liver injury (DILI). The previous study demonstrates that benzbromarone (BBR), a commonly prescribed pharmaceutical agent for managing gout and hyperuricemia, exacerbates hepatic steatosis and liver injury specifically in obese individuals. However, the precise mechanism underpinning this adverse effect remains incompletely elucidated. Given the significance of BBR and its analogs in anti‐gout/hyperuricemia drug discovery, elucidating the mechanism by which BBR exacerbates obesity‐specific DILI warrants further investigation. In this study, through a combined multi‐omics, pharmacological, and pharmacokinetic approaches, it is found that BBR‐induced obesity‐specific DILI is primarily through the potentiation of peroxisome proliferator‐activated receptor gamma (PPARγ) signaling pathways. Further in vivo and in vitro pharmacokinetic analyses reveal that obese db/db mice exhibited a diminished capacity to metabolize BBR in their livers. This reduction leads to prolonged retention of BBR, subsequently resulting in chronic and sustained hepatic PPARγ agonism. This study demonstrates that a slow metabolism‐driven amplification of hepatic PPARγ agonism mediates BBR‐induced obesity‐specific hepatic steatosis and subsequent DILI, which also emphasizes the importance of the reduced hepatic drug metabolism capacity in patients with obesity or pre‐existing NAFLD in both clinical practice and drug discovery processes.https://doi.org/10.1002/advs.202409126benzbromaronedrug‐induced liver injurydrug metabolismobesityPPARγ |
| spellingShingle | Guanting Li Yourong Hu Han Zhao Ziyu Peng Xin Shang Jia Zhang Kunxin Xie Meiwei Li Xiaohang Zhou Qinyao Zhou Kai Li Fang Zhou Heyao Wang Zhijian Xu Jiali Liu Peng Sun Slow Metabolism–Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone‐Induced Obesity‐Specific Liver Injury Advanced Science benzbromarone drug‐induced liver injury drug metabolism obesity PPARγ |
| title | Slow Metabolism–Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone‐Induced Obesity‐Specific Liver Injury |
| title_full | Slow Metabolism–Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone‐Induced Obesity‐Specific Liver Injury |
| title_fullStr | Slow Metabolism–Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone‐Induced Obesity‐Specific Liver Injury |
| title_full_unstemmed | Slow Metabolism–Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone‐Induced Obesity‐Specific Liver Injury |
| title_short | Slow Metabolism–Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone‐Induced Obesity‐Specific Liver Injury |
| title_sort | slow metabolism driven amplification of hepatic pparγ agonism mediates benzbromarone induced obesity specific liver injury |
| topic | benzbromarone drug‐induced liver injury drug metabolism obesity PPARγ |
| url | https://doi.org/10.1002/advs.202409126 |
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