Naringin Protects against Non‐Alcoholic Fatty Liver Disease by Promoting Autophagic Flux and Lipophagy

Abstract The autophagic degradation of lipid droplets, termed lipophagy, is the main mechanism contributing to lipid consumption in hepatocytes. Identifying effective and safe natural compounds that target lipophagy to eliminate excess lipids may be a potential therapeutic strategy for non‐alcoholic fatty liver disease (NAFLD). Here the effects of naringin on NAFLD and the underlying mechanisms involved are investigated. Naringin treatment effectively relieves HFD‐induced hepatic steatosis in mice and inhibits PA‐induced lipid accumulation in hepatocytes. Increased p62 and LC3‐II levels are observed with excess lipid support autophagosome accumulation and impaired autophagic flux. Treatment with naringin restores TFEB‐mediated lysosomal biogenesis, thereby promoting the fusion of autophagosomes and lysosomes, restoring impaired autophagic flux and further inducing lipophagy. However, the knockdown of TFEB in hepatocytes or the hepatocyte‐specific knockout of TFEB in mice abrogates naringin‐induced lipophagy, eliminating its therapeutic effect on hepatic steatosis. These results demonstrate that TFEB‐mediated lysosomal biogenesis and subsequent lipophagy play essential roles in the ability of naringin to mitigate hepatic steatosis and suggest that naringin is a promising drug for treating NAFLD.