期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 17, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/ijms17030387
关键词
beta-oxidation; PGC1 alpha; autophagy; hepatic steatosis; TFE3
资金
- National Natural Science Foundation of China [81270908]
- Doctoral Innovation Fund Projects from Shanghai Jiao Tong University School of Medicine [BXJ201440]
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 beta-oxidation assessment. Finally, we analyzed whether peroxisome proliferative activated receptor gamma coactivator 1 alpha (PGC1 alpha) 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 PGC1 alpha-mediated fatty acid beta-oxidation because blocking these pathways with an Atg5 small interfering RNA (siRNA) or PGC1 alpha 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.
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