Fatty acid synthase (FAS), a nutritionally regulated lipogenic enzyme, is transcriptionally controlled by ADD1/SREBP1c (adipocyte determination and differentiation 1/sterol regulatory element-binding protein 1c), through insulin-mediated stimulation of ADD1/SREBP1c expression. Progesterone exerts lipogenic effects on adipocytes, and FAS is highly induced in breast tumor cell lines upon progesterone treatment. We show here that progesterone up-regulates ADD1/SREBP1c expression in the MCF7 breast cancer cell line and the primary cultured preadipocyte from rat parametrial adipose tissue. In MCF7, progesterone induced ADD1/SREBP1c and Metallothionein II (a well known progesterone-regulated gene) mRNAs, with comparable potency. In preadipocytes, progesterone increased ADD1/SREBP1c mRNA dose-dependently, but not SREBP1a or SREBP2. Run-on experiments demonstrated that progesterone action on ADD1/SREBP1c was primarily at the transcriptional level. The membrane-bound and mature nuclear forms of ADD1/SREBP1 protein accumulated in preadipocytes cultured with progesterone, and FAS induction could be abolished by adenovirus-mediated overexpression of a dominant negative form of ADD1/SREBP1 in these cells. Finally, in the presence of insulin, progesterone was unable to up-regulate ADD1/SREBP1c mRNA in preadipocytes, whereas its effect was restored after 24 h of insulin deprivation. Together these results demonstrate that ADD1/SREBP1c is controlled by progesterone, which, like insulin, acts by increasing ADD1/SREBP1c gene transcription. This provides a potential mechanism for the lipogenic actions of progesterone on adipose tissue.
Fatty acid synthase (FAS)1 is a multifunctional enzyme that catalyzes all the steps in the synthesis of long chain fatty acids from malonyl CoA. As a key lipogenic enzyme, FAS is expressed mainly in liver and adipose tissue, where it turns dietary carbohydrates to fat. In these tissues, the transcription of the FAS gene is under nutritional control, leading to commensurately regulated activity of the enzyme. Briefly, feeding a high carbohydrate diet induces, whereas fasting or consuming a high fat diet decreases, FAS gene expression. Insulin (1), glucose (2), fatty acids (3-5), and cAMP (6) are direct effectors of the nutritional regulation of FAS, exerting coordinated effects on FAS gene transcription at the promoter level.High levels of FAS expression are also found in some tumor cells of breast cancer (7-9) and derived cell lines, where it is associated with a worsened prognosis (10). cDNA for FAS has been cloned initially as a progestin-responsive mRNA by differential screening of the MCF7 breast cancer cell line (11), and further studies have established that FAS expression was induced by progestins in the normal mammary gland also (12). The mechanism of FAS induction by progestins relies primarily on transcriptional activation, as shown by run-on studies (13). However, the direct implication of the progesterone receptor in the FAS gene-stimulated transcription has not been clearly established....