The Transcriptional Regulation And Functional Analysis Of DEPTOR

The liver is one of the most important organs in body, plays an important role in metabolism and immune response. It accepts blood from the gastrointestinal tract through the portal vein, so it’s continually exposed to pathogens, toxins and toxicants, and dietary antigens. In pathologic conditions, various liver diseases are often associated with inflammation, such as fatty liver and hepatocellular carcinoma(HCC). Some HCC patients have a higher expression level of DEPTOR in the tumorous tissues than in the tumor-adjacent tissues, especially HCC patients with hepatitis B viral infection or patients with poor prognosis. DEPTOR, a novel inhibitor of mTOR, is involved in cell survival, proliferation, adipogenesis, autophagy, and so on. Some studies have reported that DEPTOR is related to vascular endothelial cell activation and the metabolic inflammation of skeletal muscle in mice. However, it’s unclear whether DEPTOR is involved in liver inflammation. Therefore, study of whether DEPTOR participates in liver inflammation and the transcriptional regulation and function of DEPTOR in liver are not only contribute to understanding of the body’s normal physiological regulation, also help to reveal the molecular mechanism of the development of diseases related with inflammation and to provide the theoretical basis for therapy.We reported that DEPTOR mRNA and protein were significantly reduced in a mouse model of LPS-induced hepatic inflammation. In vitro, DEPTOR was also down-regulated by LPS or p65 over-expression in hepatocytes(Hepa1-6 cells). A nuclear factor for kappa B(NF-κB) antagonist(PDTC) partly blocked the effect of LPS on DEPTOR expression and several NF-κB binding sites were found in the promoter region of DEPTOR according to Bioinformatic analysis. Chromatin immunoprecipitation and luciferase reporter assays demonstrated that p65 could directly bind to the promoter of DEPTOR and reduce its activity. DEPTOR over-expression in Hepa1-6 cells increased expression of inflammatory cytokine interleukin-6(IL-6) mRNA, and monocyte chemotactic protein-1(MCP-1) mRNA and protein. Contrasting results were observed in Hepa1-6 cells with DEPTOR suppression. In addition, DEPTOR over-expression in Hepa1-6 cells increased glucose uptake, promoted glycogen accumulation, and reduced mitochondria mass.