Role of fatty acid synthesis in rapidly proliferating cells

脂肪酸在细胞中参与从能量储存和膜合成到信号转导和蛋白质结构修饰的多种功能。脂肪酸合成酶（FAS）催化从简单前体形成长链脂肪酸，在肝脏和脂肪组织中以高水平存在，用于能量的转化和储存。FAS也存在于许多其他组织中，尽管在大多数情况下，水平非常低，因为这些组织从血液中获得脂肪酸，血液中富含来自饮食的脂肪酸。然而，细胞分裂非常迅速的组织，即使在存在足够的循环脂肪酸以满足其需要的情况下，也具有高水平的FAS。例如，在月经期间形成子宫内膜的细胞和许多类型的常见人类癌症。抑制FAS的药物会抑制这些细胞的生长，最终导致细胞死亡。棕榈酸（FAS的终产物）的命运在肝脏和脂肪组织以及快速分裂的细胞之间有很大的不同。在前者中，当能量摄入过量时，脂肪酸合成发生，作为储存多余卡路里的一种手段。相比之下，在快速分裂的细胞中产生的脂肪酸似乎主要被整合到细胞膜中。然而，目前还不清楚为什么快速分裂的细胞即使在饮食中存在丰富的循环脂肪酸的情况下也会产生高水平的脂肪酸，相反，为什么当FAS被抑制时这些细胞会死亡。我们计划使用一些人乳腺癌细胞系以及正常乳腺细胞，这些细胞在FAS水平和增殖率方面存在许多差异，以探索它们如何利用短链和长链脂肪酸。这项研究将导致对快速细胞分裂条件下脂肪合成的要求以及细胞如何保持这一重要的生化过程平衡的新认识。

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.