|Institution:||Wake Forest University|
|Keywords:||Fatty Acid Synthase|
|Full text PDF:||http://hdl.handle.net/10339/39322|
Fatty acid synthesis is the process of producing de novo fatty acids from carbohydrate and protein carbon sources. The enzyme responsible for this task is appropriately termed Fatty Acid Synthase (FASN). FASN is ubiquitously expressed throughout the body, but because fatty acid synthesis is a very energy-demanding process, its stimulation in cells is heavily regulated to maintain metabolic homeostasis under normal physiological conditions. In contrast, cancer cells undergo numerous advantageous, metabolic alterations to promote the activation of the fatty acid synthesis pathway, and increase the expression of FASN. Through the development of two different Fasn knockout models, the data in this dissertation outlines the requirement of FASN to fulfill tissue-specific functions in both a normal and pathological setting. Chapter II shows that deletion of FASN in the lactating mammary gland results in lost functionality and premature involution of the gland to a near, pre-pregnancy state. Although, secretory activation was not disturbed, milk fatty acids were significantly decreased and nursing pups experienced growth retardation and perished prior to weaning, which was rescued by cross-fostering with a wild-type mother. Chapter III demonstrates the requirement of FASN for the pathological progression of prostate cancer. Prostates from Pten knockout mice showed overall decreased total prostate weight, histopathological progression, proliferation, and activation of AKT. These studies emphasize the requirement of FASN to sustain tissue-specific functions in both normal and cancer cells in vivo. Importantly, the data validates FASN as an attractive therapeutic target for the development of new cancer drugs.