Jiannan Qiu1, Jingyu Yan2, Wei Liu3, Xinzhu Liu4, Jingchao Lin5, Zeng Du6, Li Qi7, Jia Liu8, Guoxiang Xie9, Ping Liu10, Xiaoning Wang11. 1. E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: qjntcm@163.com. 2. E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanxi Technology and Business College, Taiyuan, 030006, China. Electronic address: yan9.10@foxmail.com. 3. Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: lwhzayl@163.com. 4. E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: xinzhu.liu@foxmail.com. 5. Human Metabolomics Institute, Inc., Shenzhen, Guangdong, 518109, China. Electronic address: jclin8148@163.com. 6. E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: dztcm123@163.com. 7. E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: ql_tcm@163.com. 8. E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: fionisly@hotmail.com. 9. E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Human Metabolomics Institute, Inc., Shenzhen, Guangdong, 518109, China. Electronic address: xieguoxiang@hmibiotech.com. 10. E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: liuliver@vip.sina.com. 11. E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Department of Pharmacology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: wxntcm@126.com.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Cholestasis caused by bile secretion and excretion disorders is a serious manifestation of liver disease. With limited treatment methods, it affects millions of people worldwide. Huangqi decoction (HQD), an effective traditional Chinese medicine, is used to treat chronic cholestatic liver diseases. However, the action mechanisms of it were not fully elucidated. AIM OF THE STUDY: We aim to investigate the therapeutic effect of HQD, and its active component, astragalosides, against α-naphthylisothiocyanate (ANIT)-induced cholestasis in rats based on targeted metabolomics analysis and revel the potential mechanism. MATERIALS AND METHODS: The therapeutic effect of HQD and astragalosides on ANIT-induced cholestasis model rats were evaluated by serum biochemical analysis. Liver damage was identified by histopathology. The levels of bile acids (BAs) and free fatty acids (FFAs) in serum and liver tissues were measured by ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-TQMS). qRT-PCR and Western blot analysis were used to measure the expression of nuclear hormone receptor, membrane receptor and BA transporter protein in cholestatic rats before and after HQD and astragalosides treatment. RESULTS: The obtained data showed that the administration of ANIT caused obvious cholestasis with significantly increased intrahepatic retention of hydrophobic BAs and altered FFAs, which were consistent with the liver histopathological and serum biochemical findings. HQD and astragalosides treatment were able to attenuate ANIT-induced BAs and FFAs perturbation, ameliorate the impaired liver function, histopathological ductular reaction, and lipid peroxidation damage by ANIT. Elevated mRNA and protein expression of transporters related to BA metabolism and genes related to lipogenesis and lipid oxidation metabolism in cholestasis were attenuated or normalized by HQD and astragalosides treatment. CONCLUSIONS: Intervention by ANIT can significantly change the homeostasis of BAs and FFAs. HQD and astragalosides exerted a hepatoprotective effect against cholestatic liver injury by restoring the altered BA and FFA metabolism through the improvement of BA transporter, nucleus hormone receptor, and membrane receptor.
ETHNOPHARMACOLOGICAL RELEVANCE: Cholestasis caused by bile secretion and excretion disorders is a serious manifestation of liver disease. With limited treatment methods, it affects millions of people worldwide. Huangqi decoction (HQD), an effective traditional Chinese medicine, is used to treat chronic cholestatic liver diseases. However, the action mechanisms of it were not fully elucidated. AIM OF THE STUDY: We aim to investigate the therapeutic effect of HQD, and its active component, astragalosides, against α-naphthylisothiocyanate (ANIT)-induced cholestasis in rats based on targeted metabolomics analysis and revel the potential mechanism. MATERIALS AND METHODS: The therapeutic effect of HQD and astragalosides on ANIT-induced cholestasis model rats were evaluated by serum biochemical analysis. Liver damage was identified by histopathology. The levels of bile acids (BAs) and free fatty acids (FFAs) in serum and liver tissues were measured by ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-TQMS). qRT-PCR and Western blot analysis were used to measure the expression of nuclear hormone receptor, membrane receptor and BA transporter protein in cholestaticrats before and after HQD and astragalosides treatment. RESULTS: The obtained data showed that the administration of ANIT caused obvious cholestasis with significantly increased intrahepatic retention of hydrophobic BAs and altered FFAs, which were consistent with the liver histopathological and serum biochemical findings. HQD and astragalosides treatment were able to attenuate ANIT-induced BAs and FFAs perturbation, ameliorate the impaired liver function, histopathological ductular reaction, and lipid peroxidation damage by ANIT. Elevated mRNA and protein expression of transporters related to BA metabolism and genes related to lipogenesis and lipid oxidation metabolism in cholestasis were attenuated or normalized by HQD and astragalosides treatment. CONCLUSIONS: Intervention by ANIT can significantly change the homeostasis of BAs and FFAs. HQD and astragalosides exerted a hepatoprotective effect against cholestatic liver injury by restoring the altered BA and FFA metabolism through the improvement of BA transporter, nucleus hormone receptor, and membrane receptor.