Identifying the regulatory functions of nuclear lipid synthesis and storage pathways

The nucleus contains the chromosomes necessary to transmit genetic information from one generation to the next. Similar to most cellular compartments, the nucleus is surrounded by a membrane that is composed of lipids. The membrane surrounding the nucleus keeps it separated from other compartments in the cells but also allows connections to these other compartments. It was thought that this membrane connection allowed the nucleus to receive lipids from other compartments instead of making them. However, we have shown that the nucleus contains enzymes that make lipids, and these lipids are stored within the nucleus. Furthermore, these stored lipids interact with a protein complex in the nucleus called PML that controls the ability of the cell to respond to stress, such as DNA damage. We hypothesize that the interaction between lipids and PML regulates the cell's response to fat-induced stress. Here we propose to identify the enzymes that are responsible for making and storing lipids in the nucleus, and how the activities of these enzymes are controlled. Importantly we will identify how making lipids in the nucleus affects the function of PML. These studies will identify how the production of lipids in the nucleus potentially affects the ability of liver cells to respond to excess fat and prevent its accumulation, which is a cause of disease in the liver and other organs and tissues.