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Vitamin D receptor activation down-regulates the small heterodimer partner and increases CYP7A1 to lower cholesterol.
Chow, Edwin C Y; Magomedova, Lilia; Quach, Holly P; Patel, Rucha; Durk, Matthew R; Fan, Jianghong; Maeng, Han-Joo; Irondi, Kamdi; Anakk, Sayeepriyadarshini; Moore, David D; Cummins, Carolyn L; Pang, K Sandy.
Afiliação
  • Chow EC; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
  • Magomedova L; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
  • Quach HP; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
  • Patel R; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
  • Durk MR; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
  • Fan J; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
  • Maeng HJ; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
  • Irondi K; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
  • Anakk S; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
  • Moore DD; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
  • Cummins CL; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
  • Pang KS; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. Electronic address: ks.pang@utoronto.ca.
Gastroenterology ; 146(4): 1048-59, 2014 Apr.
Article em En | MEDLINE | ID: mdl-24365583
BACKGROUND & AIMS: Little is known about the effects of the vitamin D receptor (VDR) on hepatic activity of human cholesterol 7α-hydroxylase (CYP7A1) and cholesterol metabolism. We studied these processes in mice in vivo and mouse and human hepatocytes. METHODS: Farnesoid X receptor (Fxr)(-/-), small heterodimer partner (Shp)(-/-), and C57BL/6 (wild-type control) mice were fed normal or Western diets for 3 weeks and were then given intraperitoneal injections of vehicle (corn oil) or 1α,25-dihydroxyvitamin D3 (1,25[OH]2D3; 4 doses, 2.5 µg/kg, every other day). Plasma and tissue samples were collected and levels of Vdr, Shp, Cyp7a1, Cyp24a1, and rodent fibroblast growth factor (Fgf) 15 expression, as well as levels of cholesterol, were measured. We studied the regulation of Shp by Vdr using reporter and mobility shift assays in transfected human embryonic kidney 293 cells, quantitative polymerase chain reaction with mouse tissues and mouse and human hepatocytes, and chromatin immunoprecipitation assays with mouse liver. RESULTS: We first confirmed the presence of Vdr mRNA and protein expression in livers of mice. In mice fed normal diets and given injections of 1,25(OH)2D3, liver and plasma concentrations of 1,25(OH)2D3 increased and decreased in unison. Changes in hepatic Cyp7a1 messenger RNA (mRNA) correlated with those of Cyp24a1 (a Vdr target gene) and inversely with Shp mRNA, but not ileal Fgf15 mRNA. Similarly, incubation with 1,25(OH)2D3 increased levels of Cyp24a1/CYP24A1 and Cyp7a1/CYP7A1 mRNA in mouse and human hepatocytes, and reduced levels of Shp mRNA in mouse hepatocytes. In Fxr(-/-) and wild-type mice with hypercholesterolemia, injection of 1,25(OH)2D3 consistently reduced levels of plasma and liver cholesterol and Shp mRNA, and increased hepatic Cyp7a1 mRNA and protein; these changes were not observed in Shp(-/-) mice given 1,25(OH)2D3 and fed Western diets. Truncation of the human small heterodimer partner (SHP) promoter and deletion analyses revealed VDR-dependent inhibition of SHP, and mobility shift assays showed direct binding of VDR to enhancer regions of SHP. In addition, chromatin immunoprecipitation analysis of livers from mice showed that injection of 1,25(OH)2D3 increased recruitment of Vdr and rodent retinoid X receptor to the Shp promoter. CONCLUSIONS: Activation of the VDR represses hepatic SHP to increase levels of mouse and human CYP7A1 and reduce cholesterol.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Calcitriol / Colesterol 7-alfa-Hidroxilase / Colesterol / Receptores Citoplasmáticos e Nucleares / Receptores de Calcitriol / Hepatócitos / Fígado Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Gastroenterology Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Calcitriol / Colesterol 7-alfa-Hidroxilase / Colesterol / Receptores Citoplasmáticos e Nucleares / Receptores de Calcitriol / Hepatócitos / Fígado Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Gastroenterology Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Canadá