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Non-alcoholic Fatty liver disease (NAFLD) characterized by accumulation of excessive fat in the liver is a global epidemic. NAFLD often progresses into a more severe form of steatohepatitis which can further advance into severe fibrosis, inflammation, and liver cancer. NAFLD occurs when there is increased hepatic free fatty acid (FFA) uptake and triglyceride synthesis, and increased hepatic de novo lipid synthesis from glucose (lipogenesis). Currently, there are no medical treatments available for NAFLD. Identifying proteins/enzymes that promote hepatic FFA uptake and hepatic de novo lipogenesis can lead to the development of novel therapeutic strategies to treat NAFLD. Id1 (Inhibitor of differentiation 1) is a helix-loop-helix transcription factor. Based on our initial studies, our hypothesis is that Id1 promotes hepatic FFA uptake and hepatic de novo lipogenesis, and thus, liver-specific targeting of Id1 suppresses fatty liver disease and fatty liver-associated liver tumorigenesis.  Therefore, the major goal of this project is to investigate the specific function of Id1 in the initiation and progression of fatty liver disease and fatty liver-associated liver tumorigenesis. 

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which is one of the leading causes of cancer deaths worldwide. HCC is highly resistant to conventional chemotherapies, thus emphasizing the indispensable need to discover specific molecular targets for the treatment of HCC. Using RNA-Sequencing, we detected strong upregulation of Nqo1 in DEN-induced mouse liver tumors. Most remarkably, we discovered strong inhibition of chemical-induced HCC in Nqo1 knockout mice compared to Nqo1+/+ mice, suggesting that lack of Nqo1 inhibits HCC growth. At the molecular level, Nqo1 ablation blocked activation of both the PI3K/Akt and MAPK/ERK signaling pathways. Based on these findings, our hypothesis is that Nqo1 functions as an upstream activator of both the PI3K/Akt and MAPK/ERK signaling pathways, and that Nqo1 ablation inhibits HCC cell proliferation and tumor growth; hence, Nqo1 functions as an ideal therapeutic target to inhibit HCC. Therefore, the major goal of this project is: 1. to investigate if Nqo1 is required for HCC cell proliferation and tumor growth, 2. investigate the mechanisms by which Nqo1 ablation inhibits liver cancer cell proliferation and tumor growth and 3. determine the impact of Nqo1 ablation from established liver tumors for therapeutic exploitation.