REGULATION OF FATTY-ACID SYNTHASE GENE-EXPRESSION - AN APPROACH FOR REDUCING FAT ACCUMULATION

Fatty acid synthase (FAS) catalyzes the last step in the fatty acid bi osynthetic pathway. The tissue concentration of FAS, which is affected by a number of hormonal and dietary factors, is a key determinant for the maximal capacity of a tissue to synthesize fatty acids by the de novo pathway. The complete nucleotide sequence of the avian and rat FA S transcripts has been cloned. In addition, a 1.5-kb cDNA that represe nts the thioesterase domain of the pig FAS protein plus the entire 3'- untranslated region of the transcript was isolated from a porcine live r cDNA library. Using these FAS cDNA tools, FAS mRNA transcripts have been found in most tissues, including adipose, liver, lung, brain, kid ney, and small intestine. Moreover, the abundance of FAS mRNA in a tis sue determines the rate of FAS protein synthesis; and ultimately the t issue content of FAS protein. In the liver, the rate of FAS gene trans cription dictates the level of FAS mRNA, whereas the FAS mRNA content of adipose tissue seems to be determined by factors that affect gene t ranscription and mRNA stability. Adaptive changes in the abundance of FAS mRNA seem to occur primarily in hepatic and adipose tissues, where as FAS expression in other tissue types is resistant to nutritional an d hormonal manipulations. This review presents the concept that the ti ssue-specific adaptation in FAS gene expression can be exploited to de velop a tissue-specific inhibitor of FAS gene expression and, hence, r educe the tissue capacity for fat accretion through the de novo biosyn thetic pathway. The essence of the concept is that specific transcript ional inhibitors of FAS can be identified that will suppress the trans cription of the FAS gene and, hence, decrease the hepatic or adipose t issue capacity for de novo lipogenesis. The assay termed ''targeted ge ne inhibitor assay'' can be adapted to address agents that may affect either gene transcription or mRNA stability. Unlike inhibitors of enzy me activity, such gene expression inhibitors provide an advantage of t issue specificity. Obviously, such an approach requires a detailed und erstanding of the mechanisms that govern the expression of liver or ad ipose FAS. Thus, it is the goal of this review to provide an overview of these regulatory events.