The role of the mitochondrial pyruvate carrier in the development of hepatocellullar carcinoma

Fatty liver disease, the excessive accumulation of fat in the liver, is a growing risk factor for the development of liver cancer and is often associated with metabolic diseases such as obesity and diabetes. Liver cancer often arises insidiously and is diagnosed at later stages. One protein important for normal liver metabolism that is highly expressed in liver cancer is the Mitochondrial Pyruvate Carrier (MPC). In healthy liver, the MPC facilitates normal mitochondrial metabolism of pyruvate. In non-alcoholic fatty liver disease, MPC functions facilitates aberrant metabolism causing liver damage. However, its role in liver cancer is unknown. Our research focused on understanding the MPC’s role in liver cancer. Understanding if and how the MPC facilitates the development or progression of liver cancer will provide insight into how liver cancer develops. New insight into the role of the MPC in liver cancer development provides new potential therapeutic targets. In this thesis, I demonstrate that the MPC is important for liver cancer development. I investigated how the liver-specific loss of MPC reduces the number of liver tumors in a mouse model of liver cancer. I investigated how the loss of MPC changes expression of genes in liver tumors compared to non-tumor liver. I also investigated how loss of the MPC changes the levels of glutathione, a molecule important for tumor initiation and progression, in liver tumors compared to normal liver. I also investigated the mechanism by which loss of the MPC changes liver metabolism, making it more difficult to synthesize glutathione, which impairs liver cancer development. Fatty liver disease is a leading cause for the development of liver cancer. Identifying the mechanism by which loss of the MPC reduces liver cancer development opens avenues for new therapies.