Liganded Vitamin D Receptor Through Its Interacting Repressor Inhibits the Expression of Type I Collagen α1

Area of Science:

• Molecular Biology
• Cell Biology
• Endocrinology

Background:

• Hepatic fibrosis is a reversible condition influenced by numerous transcription factors and signaling pathways.
• The Vitamin D receptor (VDR), a ligand-induced transcription factor, interacts with 9-cis retinoid X receptor (RXR) and VDR-interacting repressor (VDIR).
• VDR/RXR/VDIR complexes mediate gene expression through transactivation or transrepression, depending on VDR ligand presence.

Purpose of the Study:

• To investigate the role of VDR in regulating the expression of type I collagen genes in hepatic stellate cells (HSC-T6).
• To elucidate the mechanism by which the active form of vitamin D [1α,25(OH)2D3] affects collagen gene expression.
• To establish VDR as a potential therapeutic target for blocking or reversing hepatic fibrosis.

Main Methods:

• Time-dependent analysis of collagen gene expression in HSC-T6 cells treated with 1α,25(OH)2D3.
• Identification and characterization of the VDR response element (1αnVDRE) in the rat COLIα1 gene promoter.
• Investigation of VDR/RXR/VDIR interactions with 1αnVDRE in the presence and absence of VDR ligands.

Main Results:

• 1α,25(OH)2D3 significantly downregulated the expression of type I collagen α1 and α2 (COLIα1 and COLIα2) in HSC-T6 cells in a time-dependent manner.
• The rat COLIα1 gene promoter contains a VDR response element (1αnVDRE) comprising E-box1 and E-box2.
• Unliganded VDR/RXR may bind to 1αnVDRE via VDIR for transactivation, while liganded VDR/RXR may bind through VDIR for transrepression, indicating a reciprocal relationship.

Conclusions:

• VDR signaling is crucial in regulating collagen gene expression in hepatic stellate cells.
• The interaction between VDR/RXR and VDIR is essential for modulating COLIα1 gene expression.
• VDR represents a promising molecular target for therapeutic strategies aimed at blocking or reversing hepatic fibrosis.