Wolfberry‐Derived Zeaxanthin Dipalmitate Attenuates Ethanol‐Induced Hepatic Damage

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 µ m ) 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.