Aryl hydrocarbon receptor regulates the cholesterol biosynthetic pathway in a dioxin response element-independent manner

Authors

  • Rachel Tanos,

    1. Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Huck Institute of Life Sciences, The Pennsylvania State University, University Park, PA
    Search for more papers by this author
  • Rushang D. Patel,

    1. Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Huck Institute of Life Sciences, The Pennsylvania State University, University Park, PA
    Search for more papers by this author
  • Iain A. Murray,

    1. Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Huck Institute of Life Sciences, The Pennsylvania State University, University Park, PA
    Search for more papers by this author
  • Philip B. Smith,

    1. Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Huck Institute of Life Sciences, The Pennsylvania State University, University Park, PA
    Search for more papers by this author
  • Andrew D. Patterson,

    1. Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Huck Institute of Life Sciences, The Pennsylvania State University, University Park, PA
    Search for more papers by this author
  • Gary H. Perdew

    Corresponding author
    1. Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Huck Institute of Life Sciences, The Pennsylvania State University, University Park, PA
    • Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, The Huck Institute of Life Sciences, The Pennsylvania State University, 309A Life Sciences Building, University Park, PA 16802
    Search for more papers by this author
    • fax: 814-863-1696


  • Potential conflict of interest: Nothing to report.

  • This work was supported by a National Institutes of Health grant (ES04869) and a Bristol-Myers Squibb fellowship.

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor. Activation of AhR mediates the expression of target genes (e.g., CYP1A1) by binding to dioxin response element (DRE) sequences in their promoter region. To understand the multiple mechanisms of AhR-mediated gene regulation, a microarray analysis on liver isolated from ligand-treated transgenic mice expressing a wild-type (WT) Ahr or a DRE-binding mutant Ahr (A78D) on an ahr-null background was performed. Results revealed that AhR DRE binding is not required for the suppression of genes involved in cholesterol synthesis. Quantitative reverse-transcription polymerase chain reaction performed on both mouse liver and primary human hepatocyte RNA demonstrated a coordinated repression of genes involved in cholesterol biosynthesis, namely, HMGCR, FDFT1, SQLE, and LSS after receptor activation. An additional transgenic mouse line was established expressing a liver-specific Ahr-A78D on a CreAlb/Ahrflox/flox background. These mice displayed a similar repression of cholesterol biosynthetic genes, compared to Ahrflox/flox mice, further indicating that the observed modulation is AhR specific and occurs in a DRE-independent manner. Elevated hepatic transcriptional levels of the genes of interest were noted in congenic C57BL/6J-Ahd allele mice, when compared to the WT C57BL/6J mice, which carry the Ahb allele. Down-regulation of AhR nuclear translocator levels using short interfering RNA in a human cell line revealed no effect on the expression of cholesterol biosynthetic genes. Finally, cholesterol secretion was shown to be significantly decreased in human cells after AhR activation. Conclusion: These data firmly establish an endogenous role for AhR as a regulator of the cholesterol biosynthesis pathway independent of its DRE-binding ability, and suggest that AhR may be a previously unrecognized therapeutic target. (HEPATOLOGY 2012;55:1994–2004)

Ancillary