| Promoter variant -204A > C of the cholesterol 7α-hydroxylase gene: Association with response to plant sterols in humans and increased transcriptional activity in transfected HepG2 cells. | |
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MedLine Citation:
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PMID: 20884100 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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BACKGROUND & AIMS: The bile acid pool influences intestinal cholesterol absorption because this process is strictly dependent on micellar solubilization, which is disrupted by plant sterols (PS). Plasma lipid variation relates to promoter variant -204A > C (rs3808607) of the CYP7A1 gene encoding for 7α-hydroxylase, an enzyme for bile acid synthesis. We hypothesized that this polymorphism would be associated with variability in lipid responses to PS. METHODS: We investigated 67 subjects (31 AA and 36 AC + CC) with lipid responses to PS documented in two studies. To assess the functionality of the -204A > C variant, electrophoretic mobility gel shift assays were performed and luciferase reporter plasmids containing the promoter were transfected into HepG2 cells. RESULTS: Compared to AA-subjects, C-carriers showed significantly higher adjusted mean reductions in total cholesterol (0.14 versus 0.43 mmol/L, P = 0.042) and increases in lathosterol-to-cholesterol ratios (0.10 versus 0.75, P = 0.013). The C-construct caused a 78% promoter activity increase and gel-shift assays showed lower affinity for nuclear transcription factors, while in silico experiments predicted a binding site for inhibitory nuclear factors RXR-CAR. CONCLUSIONS: Results suggest that promoter -204A > C variant is associated with enhanced CYP7A1 activity. Increased intestinal bile acids and ensuing more efficient cholesterol absorption might explain why C-allele carriers show enhanced cholesterol lowering and increased feedback cholesterol synthesis to PS intervention. |
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Authors:
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Isabel De Castro-Orós; Sandra Pampín; Montserrat Cofán; Pilar Mozas; Xavier Pintó; Jordi Salas-Salvadó; Jose C Rodríguez-Rey; Emilio Ros; Fernando Civeira; Miguel Pocoví |
Publication Detail:
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Type: Journal Article Date: 2010-09-29 |
Journal Detail:
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Title: Clinical nutrition (Edinburgh, Scotland) Volume: 30 ISSN: 1532-1983 ISO Abbreviation: Clin Nutr Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-03-29 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8309603 Medline TA: Clin Nutr Country: England |
Other Details:
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Languages: eng Pagination: 239-46 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. |
Affiliation:
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Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, C. Pedro Cerbuna 12, 50009 Zaragoza, Spain; Instituto Aragonés de Ciencias de la Salud (I+CS), Zaragoza, Spain. |
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