Hao Gao1,2, Yi Lv3, Yingxia Liu4, Jingjing Li5, Xiaogang Wang6, Zhengqun Zhou1, George L Tipoe7, Songying Ouyang3, Yutong Guo8, Jinhong Zhang8, Xiangfeng Hao8, Wei Li9, Kazuo Koike9, Kwok-Fai So5, Jia Xiao2,7. 1. Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China. 2. Clinical Medicine Research Institute, The First Affiliated Hospital of Jinan University, Guangzhou, China. 3. Laboratory of Neuroendocrinology, School of Biological Sciences, Fujian Normal University, Fuzhou, China. 4. State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China. 5. GMH Institute of CNS Regeneration, Guangdong Medical Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, China. 6. Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Beijing, China. 7. School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong. 8. Yinchuan Bairuiyuan Biotechnology, Yinchuan, China. 9. Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan.
Abstract
SCOPE: Besides abstinence and nutritional support, there is no proven clinical treatment for patients with alcoholic fatty liver disease (AFLD). Here, the therapeutic effects and mechanisms of action of wolfberry-derived zeaxanthin dipalmitate (ZD) on AFLD models are demonstrated. METHODS AND RESULTS: The hepatoprotective effects of ZD are evaluated in vitro and in vivo. Direct interacting receptors of ZD on cell membranes are identified by liver-specific knockdown and biophysical measurements. Downstream signaling pathways are delineated using molecular and cellular biological methods. It is demonstrated that ZD attenuates hepatocyte and whole-liver injury in ethanol-treated cells (dose: 1 µm) and a chronic binge AFLD rat model (dose: 10 mg kg-1 ), respectively. The direct targets of ZD on the cell membrane include receptor P2X7 and adiponectin receptor 1 (adipoR1). Signals from P2X7 and adipoR1 modulate the phosphatidylinositide 3-kinase-Akt and/or AMP-activated protein kinase-FoxO3a pathways, to restore mitochondrial autophagy (mitophagy) functions suppressed by ethanol intoxication. In addition, ZD alleviates hepatic inflammation partially via the inhibition of Nod-like receptor 3 inflammasome, whose activation is a direct consequence of suppressed mitophagy. Liver-specific inhibition of receptors or mitophagy significantly impairs the beneficial effects of ZD. CONCLUSIONS: ZD is an effective and promising agent for the potential treatment of AFLD.
SCOPE: Besides abstinence and nutritional support, there is no proven clinical treatment for patients with alcoholic fatty liver disease (AFLD). Here, the therapeutic effects and mechanisms of action of wolfberry-derived zeaxanthin dipalmitate (ZD) on AFLD models are demonstrated. METHODS AND RESULTS: The hepatoprotective effects of ZD are evaluated in vitro and in vivo. Direct interacting receptors of ZD on cell membranes are identified by liver-specific knockdown and biophysical measurements. Downstream signaling pathways are delineated using molecular and cellular biological methods. It is demonstrated that ZD attenuates hepatocyte and whole-liver injury in ethanol-treated cells (dose: 1 µm) and a chronic binge AFLD rat model (dose: 10 mg kg-1 ), respectively. The direct targets of ZD on the cell membrane include receptor P2X7 and adiponectin receptor 1 (adipoR1). Signals from P2X7 and adipoR1 modulate the phosphatidylinositide 3-kinase-Akt and/or AMP-activated protein kinase-FoxO3a pathways, to restore mitochondrial autophagy (mitophagy) functions suppressed by ethanol intoxication. In addition, ZD alleviates hepatic inflammation partially via the inhibition of Nod-like receptor 3 inflammasome, whose activation is a direct consequence of suppressed mitophagy. Liver-specific inhibition of receptors or mitophagy significantly impairs the beneficial effects of ZD. CONCLUSIONS:ZD is an effective and promising agent for the potential treatment of AFLD.
Authors: Javier Ávila-Román; Sara García-Gil; Azahara Rodríguez-Luna; Virginia Motilva; Elena Talero Journal: Mar Drugs Date: 2021-09-23 Impact factor: 5.118