Li Fengfeng, Jiang Man, Ma Minghui, Chen Xuyang, Zhang Yidan, Zhang Yixin, Yu Yuanyuan, Cui Yunfeng, Chen Jiahui, Zhao Hui, Sun Zhijie, Dong Deli
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.
Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin 150086, China.
Acta Pharm Sin B. 2022 Mar;12(3):1322-1338. doi: 10.1016/j.apsb.2021.09.009. Epub 2021 Sep 17.
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 mice. The present study suggests that repurposing nitazoxanide as a drug for hyperlipidemia and hepatic steatosis treatment is promising.
脂质代谢紊乱会导致高脂血症和肝脂肪变性。开发同时改善高脂血症和肝脂肪变性的药物是理想的。硝唑尼特是一种经美国食品药品监督管理局（FDA）批准的口服抗原虫药物，具有优异的药代动力学特性和安全性。我们发现硝唑尼特及其代谢产物替唑尼特在HepG2细胞中诱导轻度线粒体解偶联，随后激活AMPK。经口灌胃给予硝唑尼特可抑制高脂饮食（HFD）诱导的仓鼠肝脏重量、血液和肝脏脂质增加，并改善HFD诱导的仓鼠肾脏脂质蓄积。硝唑尼特显著改善了HFD诱导的仓鼠肝脏组织病理学变化。在预先存在高脂血症和肝脂肪变性的仓鼠中，硝唑尼特也显示出治疗效果。经口灌胃给予硝唑尼特改善了C57BL/6J小鼠中HFD诱导的肝脂肪变性以及小鼠中西方饮食（WD）诱导的肝脂肪变性。本研究表明，将硝唑尼特重新用作治疗高脂血症和肝脂肪变性的药物具有前景。
