Aryl Hydrocarbon Receptor Regulates the Cholesterol Biosynthetic Pathway in a Dioxin Response Element-independent Manner

Overview

Journal Hepatology

Specialty Gastroenterology

Date 2012 Jan 12

PMID 22234961

Citations 57

Authors

Rachel Tanos

Rushang D Patel

Iain A Murray

Philip B Smith

Andrew D Patterson

Gary H Perdew

Affiliations

Soon will be listed here.

Abstract

Unlabelled: 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 Cre(Alb)/Ahr(flox/flox) background. These mice displayed a similar repression of cholesterol biosynthetic genes, compared to Ahr(flox/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-Ah(d) allele mice, when compared to the WT C57BL/6J mice, which carry the Ah(b) 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.

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References

Bennett M, Seo Y, Datta S, Shin D, Osborne T . Selective binding of sterol regulatory element-binding protein isoforms and co-regulatory proteins to promoters for lipid metabolic genes in liver. J Biol Chem. 2008; 283(23):15628-37. PMC: 2414284. DOI: 10.1074/jbc.M800391200. View

Flaveny C, Murray I, Chiaro C, Perdew G . Ligand selectivity and gene regulation by the human aryl hydrocarbon receptor in transgenic mice. Mol Pharmacol. 2009; 75(6):1412-20. PMC: 2684888. DOI: 10.1124/mol.109.054825. View

Charlton-Menys V, Durrington P . Squalene synthase inhibitors : clinical pharmacology and cholesterol-lowering potential. Drugs. 2007; 67(1):11-6. DOI: 10.2165/00003495-200767010-00002. View

Dinatale B, Schroeder J, Francey L, Kusnadi A, Perdew G . Mechanistic insights into the events that lead to synergistic induction of interleukin 6 transcription upon activation of the aryl hydrocarbon receptor and inflammatory signaling. J Biol Chem. 2010; 285(32):24388-97. PMC: 2915674. DOI: 10.1074/jbc.M110.118570. View

Olsavsky K, Page J, Johnson M, Zarbl H, Strom S, Omiecinski C . Gene expression profiling and differentiation assessment in primary human hepatocyte cultures, established hepatoma cell lines, and human liver tissues. Toxicol Appl Pharmacol. 2007; 222(1):42-56. PMC: 2974173. DOI: 10.1016/j.taap.2007.03.032. View

Ugocsai P, Hohenstatt A, Paragh G, Liebisch G, Langmann T, Wolf Z . HIF-1beta determines ABCA1 expression under hypoxia in human macrophages. Int J Biochem Cell Biol. 2009; 42(2):241-52. DOI: 10.1016/j.biocel.2009.10.002. View

Murray I, Krishnegowda G, Dinatale B, Flaveny C, Chiaro C, Lin J . Development of a selective modulator of aryl hydrocarbon (Ah) receptor activity that exhibits anti-inflammatory properties. Chem Res Toxicol. 2010; 23(5):955-66. PMC: 2871980. DOI: 10.1021/tx100045h. View

Kiortsis D, Filippatos T, Mikhailidis D, Elisaf M, Liberopoulos E . Statin-associated adverse effects beyond muscle and liver toxicity. Atherosclerosis. 2006; 195(1):7-16. DOI: 10.1016/j.atherosclerosis.2006.10.001. View

Choudhary D, Jansson I, Stoilov I, Sarfarazi M, Schenkman J . Metabolism of retinoids and arachidonic acid by human and mouse cytochrome P450 1b1. Drug Metab Dispos. 2004; 32(8):840-7. DOI: 10.1124/dmd.32.8.840. View

10.

Handschin C, Meyer U . Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR. Arch Biochem Biophys. 2004; 433(2):387-96. DOI: 10.1016/j.abb.2004.08.030. View

11.

Savouret J, Antenos M, Quesne M, Xu J, Milgrom E, Casper R . 7-ketocholesterol is an endogenous modulator for the arylhydrocarbon receptor. J Biol Chem. 2000; 276(5):3054-9. DOI: 10.1074/jbc.M005988200. View

12.

Schroeder J, Dinatale B, Murray I, Flaveny C, Liu Q, Laurenzana E . The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry. 2009; 49(2):393-400. PMC: 2805781. DOI: 10.1021/bi901786x. View

13.

Chiaro C, Morales J, Prabhu K, Perdew G . Leukotriene A4 metabolites are endogenous ligands for the Ah receptor. Biochemistry. 2008; 47(32):8445-55. DOI: 10.1021/bi800712f. View

14.

Tuomisto J, Pohjanvirta R, Unkila M, Tuomisto J . TCDD-induced anorexia and wasting syndrome in rats: effects of diet-induced obesity and nutrition. Pharmacol Biochem Behav. 1999; 62(4):735-42. DOI: 10.1016/s0091-3057(98)00224-x. View

15.

Flaveny C, Murray I, Perdew G . Differential gene regulation by the human and mouse aryl hydrocarbon receptor. Toxicol Sci. 2010; 114(2):217-25. PMC: 2840214. DOI: 10.1093/toxsci/kfp308. View

16.

Acimovic J, Fink M, Pompon D, Bjorkhem I, Hirayama J, Sassone-Corsi P . CREM modulates the circadian expression of CYP51, HMGCR and cholesterogenesis in the liver. Biochem Biophys Res Commun. 2008; 376(1):206-10. DOI: 10.1016/j.bbrc.2008.08.126. View

17.

McMillan B, Bradfield C . The aryl hydrocarbon receptor is activated by modified low-density lipoprotein. Proc Natl Acad Sci U S A. 2007; 104(4):1412-7. PMC: 1783125. DOI: 10.1073/pnas.0607296104. View

18.

Fletcher N, Wahlstrom D, Lundberg R, Nilsson C, Nilsson K, Stockling K . 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters the mRNA expression of critical genes associated with cholesterol metabolism, bile acid biosynthesis, and bile transport in rat liver: a microarray study. Toxicol Appl Pharmacol. 2005; 207(1):1-24. DOI: 10.1016/j.taap.2004.12.003. View

19.

Conway D, Sakurai Y, Weiss D, Vega J, Taylor W, Jo H . Expression of CYP1A1 and CYP1B1 in human endothelial cells: regulation by fluid shear stress. Cardiovasc Res. 2009; 81(4):669-77. PMC: 2642602. DOI: 10.1093/cvr/cvn360. View

20.

Patel R, Murray I, Flaveny C, Kusnadi A, Perdew G . Ah receptor represses acute-phase response gene expression without binding to its cognate response element. Lab Invest. 2009; 89(6):695-707. PMC: 2743259. DOI: 10.1038/labinvest.2009.24. View