Abstract
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.
MeSH terms
-
Binding Sites / genetics
-
Blotting, Western
-
Cell Line, Tumor
-
Fatty Acid Synthases / genetics
-
Fatty Acid Synthases / metabolism*
-
Gene Expression / drug effects
-
Humans
-
Luciferases / genetics
-
Luciferases / metabolism
-
Mutation
-
Promoter Regions, Genetic / genetics*
-
Protein Binding
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
Receptors, Retinoic Acid / genetics
-
Receptors, Retinoic Acid / metabolism
-
Recombinant Fusion Proteins / genetics
-
Recombinant Fusion Proteins / metabolism
-
Retinoid X Receptors / genetics
-
Retinoid X Receptors / metabolism
-
Reverse Transcriptase Polymerase Chain Reaction
-
Sterol Regulatory Element Binding Protein 1 / genetics
-
Sterol Regulatory Element Binding Protein 1 / metabolism*
-
Transfection
-
Tretinoin / pharmacology*
Substances
-
RNA, Messenger
-
Receptors, Retinoic Acid
-
Recombinant Fusion Proteins
-
Retinoid X Receptors
-
SREBF1 protein, human
-
Sterol Regulatory Element Binding Protein 1
-
Tretinoin
-
Luciferases
-
Fatty Acid Synthases