SREBP-1c mediates the retinoid-dependent increase in fatty acid synthase promoter activity in HepG2

Treatment of HepG2 with all-trans retinoic acid (RA) induces expression of fatty acid synthase (FAS) mRNA and protein. Transfections show that the FAS promoter positively responds to retinoid X receptor (RXR) but not to RA receptor (RAR) agonists. Since RXR alone is capable of mediating the RA response of FAS, the existence of a classical RA-responsive element in the FAS promoter may be ruled out. Binding sites for NF-Y and SREBP-1 proved to be essential for the RA response. Exposure to all-trans RA increased mRNA and protein levels of SREBP-1, a transcriptional activator for FAS. Overexpression of a dominant-negative form of SREBP-1c diminished the RA-dependent increase in promoter activity. These data demonstrate that RXR ligands can stimulate the expression of a lipogenic gene solely by inducing transcription and cleavage of membrane-bound SREBP-1c.