Identification of a novel enhancer sequence in the distal promoter of the rat fatty acid synthase gene

The proximal promoter and first intron of the fatty acid synthase (FAS) gene contains response sequences for insulin and glucose, but the 2- to 3-fold increase in FAS promoter activity attributable to these sequences falls short of the 20- to 30-fold induction in hepatic FAS gene transcription observed in fasted-refed rats. Using DNase I hypersensitivity site (HSS) mapping, two new liver specific sites were localized to the regions of: -8600 to -8500 (HSS 1) and -7300 to -7000 (HSS 2). DNase sensitivity of the -7300 to -7000 region was increased when fasted rats were refed glucose. When rat hepatocytes were transfected with a CAT construct that linked the region of -9700 and -4606 with the insulin response region located between -265 to +65, FAS promoter activity was induced 15-fold. This increase required the presence of both insulin and glucocorticoids. Deleting HSS 2 abolished the 15-fold induction in FAS promoter activity, but removing HSS 1 was without effect. Apparently the in vivo regulation of hepatic FAS gene transcription requires response elements located in the region of -7300 to -7000 and -265 to +65.