Transcriptional regulation of human oxysterol 7alpha-hydroxylase by sterol response element binding protein.
Oxysterol 7alpha-hydroxylase (CYP7B1) metabolizes oxysterols, potent regulators of lipid homeostasis. Very little is known about transcriptional regulation of human CYP7B1. The present results indicate that sterol response element binding protein (SREBP), a family of oxysterol-responsive transcription factors that stimulates cholesterol synthesis, may be an important regulator of CYP7B1. SREBP suppressed a human CYP7B1 luciferase reporter gene in several cell lines, most markedly in rat hepatoma McA-RH7777 cells. An SREBP-1-responsive region was mapped to a GC-rich sequence in the proximal CYP7B1 promoter, containing binding sites for the basal transcriptional activator Sp1. Mutagenesis of this sequence abolished SREBP-1-mediated suppression. Data indicated that SREBP does not bind this sequence but affects the gene indirectly, probably via interaction with Sp1. Our findings indicate that CYP7B1 transcription is controlled by SREBP and reveal a link between oxysterol-sensitive regulators and oxysterol metabolism. We propose that CYP7B1 is important for regulating cellular sterol content and protects against oxysterol-mediated toxicity.
Department of Biochemistry and Molecular Pathology, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA. Maria.Norlin@farmbio.uu.se
Maria
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Norlin
John Y L
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Chiang
D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000502:physiology; D000072474:Cytochrome P450 Family 7; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004794:Enzyme Repression; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011401:Promoter Regions, Genetic; D020218:Response Elements; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000502:physiology; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; C497387:SREBF1 protein, human; D016329:Sp1 Transcription Factor; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C115867:oxysterol 7-alpha-hydroxylase; D000072474:Cytochrome P450 Family 7; C499571:CYP7B1 protein, human