Liver X receptor alpha interferes with SREBP1c-mediated Abcd2 expression. Novel cross-talk in gene regulation

Area of Science:

• Molecular Biology
• Gene Regulation
• Biochemistry

Background:

• The ABCD2 gene encodes a peroxisomal ATP binding cassette transporter.
• ABCD2 shows functional redundancy with the X-linked adrenoleukodystrophy-associated protein, suggesting therapeutic potential through ABCD2 up-regulation.
• Cholesterol lowering activates ABCD2 in cultured cells, indicating sterol-mediated regulation.

Purpose of the Study:

• To investigate the in vivo regulation of ABCD2 by sterols.
• To characterize the sterol regulatory element (SRE) in the murine Abcd2 promoter.
• To elucidate the cross-talk between sterol regulatory element-binding proteins (SREBPs) and liver X receptor (LXR)/retinoid X receptor (RXR) in Abcd2 gene regulation.

Main Methods:

• Characterization of the murine Abcd2 promoter, including identification of a sterol regulatory element (SRE).
• Investigation of SREBP and LXR/RXR binding to the SRE/direct repeat 4 element.
• Utilizing fasting-refeeding and cholesterol loading models in mice.
• Analysis of Abcd2 expression in wild-type and LXRα,β-deficient mice.

Main Results:

• A sterol regulatory element (SRE) in the murine Abcd2 promoter was identified, bound by SREBPs and overlapping with an LXR/RXR binding site.
• Adipose Abcd2 is induced by SREBP1c, while hepatic Abcd2 is down-regulated by concurrent activation of LXRα and SREBP1c.
• Ligand-activated LXRα counteracts SREBP1c-mediated Abcd2 induction in cell culture.
• Hepatic Abcd2 expression in LXRα,β-deficient mice was significantly higher than in wild-type mice.

Conclusions:

• Liver X receptor alpha (LXRα) acts as a negative modulator of Abcd2 expression.
• A novel regulatory mechanism involving overlapping SREBP and LXRα binding sites on the Abcd2 promoter has been identified.
• This study reveals intricate cross-talk between SREBP and LXR/RXR signaling pathways in the regulation of Abcd2.