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Autophagy flux deficiency is closely related to the development of hepatic steatosis. Transcription factor E3 ( TFE3 ) is reported to be a crucial gene that regulates autophagy flux and lysosome function. Therefore, we investigated the role of  TFE3  in a cell model of hepatic steatosis. We constructed L02 hepatocyte lines that stably over-expressed or knocked down the expression of  TFE3 . Subsequently, the effects of  TFE3  on hepatocellular lipid metabolism were determined by autophagy flux assay, lipid oil red O (ORO) staining, immunofluorescence staining, and mitochondrial β-oxidation assessment. Finally, we analyzed whether peroxisome proliferative activated receptor gamma coactivator 1α ( PGC1α ) was the potential target gene of  TFE3  in the regulation of hepatic steatosis using a chromatin immunoprecipitation (CHIP) assay and a luciferase reporter system. We found that overexpression of  TFE3  markedly alleviated hepatocellular steatosis. On the contrary, downregulation of  TFE3  resulted in an aggravated steatosis. The mechanistic studies revealed that the  TFE3 -manipulated regulatory effects on hepatocellular steatosis are dependent on autophagy-induced lipophagy and  PGC1α -mediated fatty acid β-oxidation because blocking these pathways with an  Atg5  small interfering RNA (siRNA) or  PGC1α  siRNA dramatically blunted the  TFE3 -mediated regulation of steatosis. In conclusion,  TFE3  gene provides a novel insight into the treatment of hepatic steatosis and other metabolic disease.

TFE3 Alleviates Hepatic Steatosis through Autophagy-Induced Lipophagy and PGC1α-Mediated Fatty Acid β-Oxidation