Format

Send to:

Choose Destination
See comment in PubMed Commons below
Mol Endocrinol. 2010 Jun;24(6):1151-64. doi: 10.1210/me.2009-0482. Epub 2010 Apr 6.

A novel bile acid-activated vitamin D receptor signaling in human hepatocytes.

Author information

  • 1Department of Integrative Medical Sciences, Northeastern Ohio University's Colleges of Medicine and Pharmacy, 4209 State Route 44, Rootstown, Ohio 44272, USA.

Abstract

Vitamin D receptor (VDR) is activated by natural ligands, 1alpha, 25-dihydroxy-vitamin D(3) [1alpha,25(OH)(2)-D(3)] and lithocholic acid (LCA). Our previous study shows that VDR is expressed in human hepatocytes, and VDR ligands inhibit bile acid synthesis and transcription of the gene encoding cholesterol 7alpha-hydroxylase (CYP7A1). Primary human hepatocytes were used to study LCA and 1alpha,25(OH)(2)-D(3) activation of VDR signaling. Confocal immunofluorescent microscopy imaging and immunoblot analysis showed that LCA and 1alpha, 25(OH)(2)-D(3) induced intracellular translocation of VDR from the cytosol to the nucleus and also plasma membrane where VDR colocalized with caveolin-1. VDR ligands induced tyrosine phosphorylation of c-Src and VDR and their interaction. Inhibition of c-Src abrogated VDR ligand-dependent inhibition of CYP7A1 mRNA expression. Kinase assays showed that VDR ligands specifically activated the c-Raf/MEK1/2/extracellular signal-regulated kinase (ERK) 1/2 pathway, which stimulates serine phosphorylation of VDR and hepatocyte nuclear factor-4alpha, and their interaction. Mammalian two-hybrid assays showed a VDR ligand-dependent interaction of nuclear receptor corepressor-1 and silencing mediator of retinoid and thyroid with VDR/retinoid X receptor-alpha (RXRalpha). Chromatin immunoprecipitation assays revealed that an ERK1/2 inhibitor reversed VDR ligand-induced recruitment of VDR, RXRalpha, and corepressors to human CYP7A1 promoter. In conclusion, VDR ligands activate membrane VDR signaling to activate the MEK1/2/ERK1/2 pathway, which stimulates nuclear VDR/RXRalpha recruitment of corepressors to inhibit CYP7A1 gene transcription in human hepatocytes. This membrane VDR-signaling pathway may be activated by bile acids to inhibit bile acid synthesis as a rapid response to protect hepatocytes from cholestatic liver injury.

PMID:
20371703
[PubMed - indexed for MEDLINE]
PMCID:
PMC2875805
Free PMC Article

Publication Types, MeSH Terms, Substances, Grant Support

Publication Types

MeSH Terms

Substances

Grant Support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for Atypon Icon for PubMed Central
    Loading ...
    Write to the Help Desk