Regulation of ATP-binding Cassette Sterol Transporters ABCG5 and ABCG8 by the Liver X Receptors α and β

TLDR

Mutations in the ABCG5 and ABCG8 transporters cause the autosomal recessive disorder sitosterolemia. The study demonstrates that ABCG5 and ABCG8 are direct transcriptional targets of the oxysterol receptors LXRα and LXRβ. Using high‑cholesterol diets, synthetic LXR ligands, and LXR agonist‑treated mice, the authors show that LXRα/β directly regulate ABCG5/G8 gene expression. High‑cholesterol diets and LXR agonists markedly up‑regulate ABCG5/G8 mRNA in mouse liver and intestine, localized to hepatocytes and enterocytes, an effect absent in LXR‑deficient mice; cycloheximide‑resistant transcription confirms direct regulation, underscoring LXRs as sterol sensors coordinating cholesterol metabolism.

Abstract

Mutations in the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 have recently been shown to cause the autosomal recessive disorder sitosterolemia. Here we demonstrate that the ABCG5 and ABCG8 genes are direct targets of the oxysterol receptors liver X receptor (LXR) α and LXRβ. Diets containing high cholesterol markedly increased the expression of ABCG5/G8 mRNA in mouse liver and intestine. This increase was also observed using synthetic ligands of LXR and its heterodimeric partner, the retinoid X receptor. <i>In situ</i> hybridization analyses of tissues from LXR agonist-treated mice revealed that ABCG5/G8 mRNA is located in hepatocytes and enterocytes and is increased upon LXR activation. In addition, expression of the LXR target gene ABCA1, previously implicated in the control of cholesterol absorption, was also dramatically up-regulated in jejunal enterocytes upon exposure to LXR agonists. These changes in ABC transporter gene expression were not observed in mice lacking LXRs. Furthermore, in the rat hepatoma cell line FTO2B, LXR-dependent transcription of the ABCG5/G8 genes was cycloheximide-resistant, indicating that these genes are directly regulated by LXRs. The addition of ABCG5 and ABCG8 to the growing list of LXR target genes further supports the notion that LXRs serve as sterol sensors to coordinately regulate sterol catabolism, storage, efflux, and elimination.