کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
3299322 | 1209926 | 2008 | 15 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Regulation of Bile Acid Synthesis by the Nuclear Receptor Rev-erbα
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کلمات کلیدی
موضوعات مرتبط
علوم پزشکی و سلامت
پزشکی و دندانپزشکی
بیماریهای گوارشی
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چکیده انگلیسی
Background & Aims: Conversion into bile acids represents an important route to remove excess cholesterol from the body. Rev-erbα is a nuclear receptor that participates as one of the clock genes in the control of circadian rhythmicity and plays a regulatory role in lipid metabolism and adipogenesis. Here, we investigate a potential role for Rev-erbα in the control of bile acid metabolism via the regulation of the neutral bile acid synthesis pathway. Methods: Bile acid synthesis and CYP7A1 gene expression were studied in vitro and in vivo in mice deficient for or over expressing Rev-erbα. Results: Rev-erbα-deficient mice display a lower synthesis rate and an impaired excretion of bile acids into the bile and feces. Expression of CYP7A1, the rate-limiting enzyme of the neutral pathway, is decreased in livers of Rev-erbα-deficient mice, whereas adenovirus-mediated hepatic Rev-erbα overexpression induces its expression. Moreover, bile acid feeding resulted in a more pronounced suppression of hepatic CYP7A1 expression in Rev-erbα-deficient mice. Hepatic expression of E4BP4 and the orphan nuclear receptor small heterodimer partner (SHP), both negative regulators of CYP7A1 expression, is increased in Rev-erbα-deficient mice. Promoter analysis and chromatin immunoprecipitation experiments demonstrated that SHP and E4BP4 are direct Rev-erbα target genes. Finally, the circadian rhythms of liver CYP7A1, SHP, and E4BP4 messenger RNA levels were perturbed in Rev-erbα-deficient mice. Conclusions: These data identify a role for Rev-erbα in the regulatory loop of bile acid synthesis, likely acting by regulating both hepatic SHP and E4BP4 expression.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Gastroenterology - Volume 135, Issue 2, August 2008, Pages 689-698.e5
Journal: Gastroenterology - Volume 135, Issue 2, August 2008, Pages 689-698.e5
نویسندگان
Hélène Duez, Jelske N. van der Veen, Christian Duhem, Benoît Pourcet, Thierry Touvier, Coralie Fontaine, Bruno Derudas, Eric Baugé, Rick Havinga, Vincent W. Bloks, Henk Wolters, Fjodor H. van der Sluijs, Björn Vennström, Folkert Kuipers,