Tangeretin Protects Mice from Alcohol-Induced Fatty Liver by Activating Mitophagy through the AMPK–ULK1 Pathway

studies performed on ethanol-treated hepatic AML-12 cells. Ethanol feeding increased the serum alanine aminotransferase and aspartate aminotransferase levels, the liver weight, and the serum and liver triacylglycerol contents, whereas 20 and 40 mg/kg tangeretin treatment promoted a dose-dependent suppression of these effects. Interestingly, tangeretin prevented increases in the liver oxidative stress level and protected the hepatocyte mitochondria from ethanol-induced morphologic abnormalities. A mechanistic study showed that 20 μM tangeretin treatment activated mitophagy through an AMP-activated protein kinase (AMPK)-uncoordinated 51-like kinase 1 (Ulk1) pathway, thereby restoring mitochondria respiratory function and suppressing steatosis. By contrast, blocking the AMPK-Ulk1 pathway with compound C reversed the hepatoprotective effect of tangeretin. Overall, tangeretin activated mitophagy and protected against ethanol-induced hepatic steatosis through an AMPK-Ulk1-dependent mechanism.