Original articles
Fengfeng Li, Man Jiang, Minghui Ma, Xuyang Chen, Yidan Zhang, Yixin Zhang, Yuanyuan Yu, Yunfeng Cui, Jiahui Chen, Hui Zhao, Zhijie Sun, Deli Dong. Anthelmintics nitazoxanide protects against experimental hyperlipidemia and hepatic steatosis in hamsters and mice[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1322-1338

Anthelmintics nitazoxanide protects against experimental hyperlipidemia and hepatic steatosis in hamsters and mice
Fengfeng Lia,b, Man Jianga,b, Minghui Maa,b, Xuyang Chena,b, Yidan Zhanga,b, Yixin Zhanga,b, Yuanyuan Yua,b, Yunfeng Cuia,b, Jiahui Chena,b, Hui Zhaoa,b, Zhijie Sunc, Deli Donga,b,c
a. Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China;
b. Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150086, China;
c. Department of Pharmacology, China Pharmaceutical University, Nanjing 211198, China
Abstract:
Lipid metabolism disorders contribute to hyperlipidemia and hepatic steatosis. It is ideal to develop drugs simultaneous improving both hyperlipidemia and hepatic steatosis. Nitazoxanide is an FDA-approved oral antiprotozoal drug with excellent pharmacokinetic and safety profile. We found that nitazoxanide and its metabolite tizoxanide induced mild mitochondrial uncoupling and subsequently activated AMPK in HepG2 cells. Gavage administration of nitazoxanide inhibited high-fat diet (HFD)-induced increases of liver weight, blood and liver lipids, and ameliorated HFD-induced renal lipid accumulation in hamsters. Nitazoxanide significantly improved HFD-induced histopathologic changes of hamster livers. In the hamsters with pre-existing hyperlipidemia and hepatic steatosis, nitazoxanide also showed therapeutic effect. Gavage administration of nitazoxanide improved HFD-induced hepatic steatosis in C57BL/6J mice and western diet (WD)-induced hepatic steatosis in Apoe-/- mice. The present study suggests that repurposing nitazoxanide as a drug for hyperlipidemia and hepatic steatosis treatment is promising.
Key words:    Nitazoxanide    Tizoxanide    Hyperlipidemia    Hepatic steatosis    AMPK    Autophagy    SQSTM1/P62    Mitochondrial uncoupling   
Received: 2021-05-22     Revised: 2021-07-16
DOI: 10.1016/j.apsb.2021.09.009
Funds: This study was supported by the National Natural Science Foundation of China (Nos. 81773725 and 91739102).
Corresponding author: Zhijie Sun,E-mai:sunzhijie@cpu.edu.cn;Deli Dong,E-mai:dongdeli@ems.hrbmu.edu.cn     Email:sunzhijie@cpu.edu.cn;dongdeli@ems.hrbmu.edu.cn
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Fengfeng Li
Man Jiang
Minghui Ma
Xuyang Chen
Yidan Zhang
Yixin Zhang
Yuanyuan Yu
Yunfeng Cui
Jiahui Chen
Hui Zhao
Zhijie Sun
Deli Dong

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