Differential effects of sterol regulatory binding proteins 1 and 2 on sterol 12 alpha-hydroxylase. SREBP-2 suppresses the sterol 12 alpha-hydroxylase promoter.
The most important pathway for the catabolism and excretion of cholesterol in mammals is the formation of bile acids. Improper regulation of this pathway has implications for atherosclerosis, cholesterol gallstone formation, and some lipid storage diseases. Sterol 12 alpha-hydroxylase (12 alpha-hydroxylase) is required for cholic acid biosynthesis. The alpha(1)-fetoprotein transcription factor FTF is crucial for the expression and the bile acid-mediated down-regulation of 12 alpha-hydroxylase. Cholesterol, on the other hand, down-regulates expression of the 12 alpha-hydroxylase gene. In this study, we show that the two sterol regulatory binding proteins (SREBPs) have opposite effects on the 12 alpha-hydroxylase promoter. SREBP-1 activated the 12 alpha-hydroxylase promoter, as it does with many other cholesterol-regulated genes. In contrast, SREBP-2 suppressed 12 alpha-hydroxylase promoter activity. SREBP-1 mediates the cholesterol-down-regulation of 12 alpha-hydroxylase promoter by binding to two inverted sterol regulatory elements found approximately 300 nucleotides from the transcriptional initiation site. SREBP-2 mediated suppression of 12 alpha-hydroxylase without binding to its promoter. Data are presented suggesting that SREBP-2 suppresses the 12 alpha-hydroxylase promoter by interacting with FTF. This is the first report of a promoter responding oppositely to two members of the SREBP family of transcription factors. These studies provide a novel function and mode of action of a SREBP protein.
del Castillo-Olivares
Antonio
A
Department of Biochemistry and Molecular Biophysics, Medical College of Virginia, Richmond, Virginia 23298-0614, USA.
Gil
Gregorio
G
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D007700:Kinetics; D016350:Leucine Zippers; D008113:Liver Neoplasms; D008156:Luciferases / Q000235:genetics; D008322:Mammals; D016296:Mutagenesis; D016297:Mutagenesis, Site-Directed; D015345:Oligonucleotide Probes; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013253:Steroid 12-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics*; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D013489:Suppression, Genetic; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D015345:Oligonucleotide Probes; D011993:Recombinant Fusion Proteins; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D008156:Luciferases; D013250:Steroid Hydroxylases; D013253:Steroid 12-alpha-Hydroxylase