Role of fatty acid synthesis in rapidly proliferating cells

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Fatty acids are involved in diverse functions in cells from energy storage and membrane synthesis to signal transduction and modification of protein structure. The enzyme fatty acid synthase (FAS) that catalyzes the formation of long chain fatty acids from simple precursors, is present at high levels in liver and fatty tissues for the conversion and storage of energy. FAS is also present in many other tissues although in most, at very low levels because these tissues derive their fatty acids from the blood that is rich in fatty acids from the diet. Tissues in which cells are dividing very rapidly, however, have high levels of FAS even in the presence of sufficient circulating fatty acids to meet their needs. Examples are the cells that form the lining of the womb during menstruation and many types of common human cancers. Drugs that inhibit FAS inhibit the growth of these cells and ultimately lead to cell death. The fate of palmitic acid, the end product of FAS, differs substantially between liver and fatty tissues and rapidly dividing cells. In the former, fatty acid synthesis occurs when energy intake is in excess as a means to store excess calories. In contrast, the fatty acids that are made in rapidly dividing cells seem to be mainly incorporated into membranes. It remains unclear, however, why rapidly dividing cells produce high levels of fatty acids even in the presence of abundant circulating fatty acids from the diet and, conversely, why these cells die when FAS in inhibited. We plan to use a number of human breast cancer cell lines as well as normal breast cells that differ many-fold in their levels of FAS and proliferation rates to explore how they utilize short and long chain fatty acids. This research will lead to a new understanding of the requirements for fat synthesis under conditions of rapid cell division and how cells keep this important biochemical process in balance.