Cloning and characterization of the human stearoyl-CoA desaturase gene promoter: transcriptional activation by sterol regulatory element binding protein and repression by polyunsaturated fatty acids and cholesterol.
Stearoyl-CoA desaturase (SCD) is a microsomal enzyme required for the biosynthesis of oleate (C18:1) and palmitoleate (C16:1) which are the major monounsaturated fatty acids of membrane phospholipids, triglycerides and cholesterol esters. Previously the full-length human skin cDNA was sequenced and the exon and intron structure of the single functional SCD gene determined. Here we report on the cloning and characterization of the promoter region of the human SCD gene. The human promoter structure is very similar to that of the mouse SCD1 isoform and contains conserved regulatory sequences for the binding of several transcription factors including the sterol regulatory element binding protein (SREBP), CCAAT enhancer binding protein-alpha (C/EBPalpha) and nuclear factor-1 (NF-1) that have been shown to transactivate the transcription of the mouse SCD1 gene. Polyunsaturated fatty acids and cholesterol decreased the SCD promoter-luciferase activity when transiently transfected into HepG2 cells. The decrease in promoter activity correlated with decreases in endogenous SCD mRNA and protein levels. Cotransfection experiment in HepG2 cells showed transactivation of the SCD promoter-luciferase activity by an expression vector containing SREBP-1a and 1c. Our studies indicate that the transcription of the human SCD gene is repressed by polyunsaturated fatty acids and cholesterol and that SREBP plays a role in the transcriptional activation of this gene.
Bené
H
H
Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin 53706, USA.
Lasky
D
D
Ntambi
J M
JM
D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D002784:Cholesterol / Q000502:physiology*; D003001:Cloning, Molecular; D004247:DNA / Q000032:analysis; D004268:DNA-Binding Proteins / Q000502:physiology*; D005231:Fatty Acids, Unsaturated / Q000502:physiology*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D013230:Stearoyl-CoA Desaturase / Q000235:genetics*; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D015533:Transcriptional Activation
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005231:Fatty Acids, Unsaturated; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D004247:DNA; D002784:Cholesterol; D013230:Stearoyl-CoA Desaturase