Abstract
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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease with increasing incidence worldwide; it ranges from simple steatosis to steatohepatitis with progressive fibrosis and, cirrhosis [1]
We show that over-expression of Transcription factor E3 (TFE3) ameliorates the steatosis in hepatocytes exposed to free fatty acids (FFAs)
Autophagy Flux Is Impaired in Free Fatty Acids (FFAs) Induced Hepatocellular Steatosis and Transcription Factor E3 (TFE3) May Be Involved in Dysfunctional Hepatic Lipid Metabolism
Summary
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease with increasing incidence worldwide; it ranges from simple steatosis to steatohepatitis with progressive fibrosis and, cirrhosis [1]. Autophagy induction via liver-specific over-expression of Atg or pharmacological agents such as rapamycin and carbamazepine improves the metabolic state and reduces steatosis [12,13,14]. These findings further demonstrate a lipolytic function of autophagy; therapeutic strategies aimed at increasing autophagic functions may provide an attractive approach to prevent NAFLD and its associated pathologies. Transcription factor E3 (TFE3) is a member of the basic helix-loop-helix leucine zipper family of transcription factors It recognizes a 10-base pair motif (GTCACGTGAC) known as the coordinated lysosomal expression and regulation (CLEAR) element that is enriched in the promoters of numerous autophagy-lysosomal pathway-related genes. We demonstrate that the effects of TFE3 on hepatic steatosis dependent on the autophagy-induced lipophagy and PGC1α-mediated fatty acid β-oxidation
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